5-HT receptor ligands and uses thereof

ABSTRACT

Compounds of Formula (IA) that act as 5-HT receptor ligands and their uses in the treatment of diseases linked to the activation of 5-HT 2  receptors in animals are described herein.

This application claims the benefit of U.S. Provisional Ser. No.60/299,953 filed on Jun. 21, 2001 and incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pyrimidine compounds that act as 5-HTreceptor ligands, in particular 5-HT_(2c) receptor ligands, and theiruses in the prevention or treatment of diseases linked to the activationof 5-HT_(2c) receptors in animals.

BACKGROUND

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein-coupled receptors. Serotonin is thought to play arole in processes related to learning and memory, sleep,thermoregulation, mood, motor activity, pain, sexual and aggressivebehaviors, appetite, neurodegenerative regulation, and biologicalrhythms. As expected, serotonin is linked to pathophysiologicalconditions such as anxiety, depression, obsessive-compulsive disorders,schizophrenia, suicide, autism, migraine, emesis, alcoholism andneurodegenerative disorders.

The serotonin receptors are currently classified into seven subfamilies(5-HT₁ through 5-HT₇). See, Hoyer, D., et al., “VII International Unionof Pharmacology classification of receptors for 5-hydroxytryptamine”,Pharmacol. Rev., 56, 157-203 (1994). The subfamilies have been furtherdivided into subtypes. For example, the 5-HT₂ receptor is currentlydivided into three subtypes: 5-HT_(2a), 5-HT_(2b) and 5-HT_(2c). Thethree subtypes of 5-HT₂ receptors are linked to phospholipase C with thegeneration of two second messengers, diacylglycerol (which activatesprotein kinase C) and inositol trisphosphate (which releasesintracellular stores of Ca²⁺). The 5-HT_(2c) receptors have a very highdensity in the choroid plexus, an epithelial tissue that is the primarysite of cerebrospinal fluid production. See, Sanders-Bush, E. and S. E.Mayer, “5-Hydroxytryptamine (Serotonin) Receptor agonists andAntagonists”, Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Chapter 11, 9^(th) Ed., McGraw-Hill, New York, N.Y.(1996).

Julius, et al., isolated and characterized the 5-HT_(2c) receptor andlater reported that transgenic mice lacking the 5-HT_(2c) receptorexhibit seizures and an eating disorder resulting in increasedconsumption of food (see, U.S. Pat. Nos. 4,985,352 and 5,698,766,respectively). Consequently, compounds selective for the 5-HT_(2c)receptor may provide useful therapies for the treatment of seizure andeating disorders without the side effects typically associated withnonselectivity of the ligand.

Several compounds have been proposed as 5-HT_(2c) receptor agonists orantagonists for use in the treatment of obesity and other relateddiseases associated with decreased neurotransmission of serotonin inmammals. See, e.g., EP 863136 (azetidine and pyrrolidine derivatives);EP 657426 (tricyclic pyrrole derivatives); EP 655440 (substituted1-aminoethyl indoles); EP 572863 (pyrazinoindole derivatives);WO98/030548 (aminoalkylindazole compounds); WO 98/56768 (tricyclicpyrrole and pyrazole derivatives); WO 99/43647 (azetidine andpyrrolidine derivatives); WO 99/58490 (aryl-hydronaphthalenalkanaminederivatives); WO 00/12475 (indoline derivatives); WO 00/12482 (indazolederivatives); WO 00/12502 (pyrroloquinoline derivatives); WO 00/12510(pyrroloindole, pyridoindole and azepinoindole derivatives); WO 00/28993(naphthylacetylpiperazine derivatives); WO 00/44737(aminoalkylbenzofuran derivatives); and WO 00/76984 (2,3-disubstitutedpyrazines).

The non-selectivity of ligands for the various 5-HT receptors remains achallenge. It is suspected that the non-selectivity of some ligandscontributes to various adverse side effects such as hallucinations andcardiovascular complications. Therefore, there remains a need for5-HT_(2c) selective receptor ligands.

SUMMARY

The present invention provides compounds of Formula (IA) which areuseful as 5-HT₂ receptor ligands (in particular, 5-HT_(2a) and 5-HT_(2c)receptor ligands).

wherein

-   -   X and Y are CR and Z is N, or X is N and Y and Z are CR, where R        for each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino,        or (C₁-C₄)alkylamino;    -   W is oxy, thio, amino, (C₁-C₄)alkylamino, or acetylamino;    -   at least one of R^(1a), R^(1b), R^(1d), and R^(1e) is        independently selected from the group consisting of halogen,        nitro, amino, cyano, —C(O)NH₂, (C₁-C₄)alkyl,        halo-substituted(C₁-C₄)alkyl, (C₁-C₄) alkoxy, and        halo-substituted(C₁-C₄)alkoxy, or R^(1a) and R^(1b) taken        together form a five- or six-membered, aromatic or partially or        fully saturated fused ring, or R^(1a) taken together with R^(2a)        or R^(2b) forms a five- or six-membered, fully saturated fused        ring;    -   R^(1c) is hydrogen;    -   R^(2a) and R^(2b) are each independently hydrogen, (C₁-C₄)alkyl,        partially or fully saturated (C₃-C₆)cycloalkyl, or one of which        taken together with R^(1a) forms a five- or six-membered, fully        saturated fused ring;    -   n is 0, 1, or 2;    -   R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,        or (C₁-C₄)alkyl substituted with hydroxy, fluoro, or        (C₁-C₄)alkoxy;    -   R⁴ is hydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted        with hydroxy or cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxy-carbonyl, (C₃-C₄)alkenyl, or an amino-protecting        group;    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Preferred compounds of Formula (IA) are those where X and Y are CR and Zis N, or X is N and Y and Z are CR, where R is hydrogen, chloro, fluoro,or methyl;

-   -   (i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl, methoxy,        or trifluoromethoxy, and R^(1b), R^(1d) and R^(1e) are each        hydrogen,    -   (ii) R^(1b) is halogen, methyl, or methoxy and R^(1a), R^(1d)        and R^(1e) are each hydrogen,    -   (iii) R^(1a) and R^(1b) are each independently halogen or methyl        and R^(1d) and R^(1e) are each hydrogen,    -   (iv) R^(1b) and R^(1d) are each independently halogen or methyl        and R^(1a) and R^(1e) are each hydrogen,    -   (v) R^(1a) and R^(1d) are each independently halogen or methyl        and R^(1b) and R^(1e) are each hydrogen,    -   (vi) R^(1a) and R^(1e) are each independently halogen or methyl        and R^(1b) and R^(1d) are each hydrogen, or    -   (vii) R^(1a), R^(1b) and R^(1d) are each independently halogen        or methyl and R^(1e) is hydrogen;

-   W is oxy or amino; n is 1; R^(2a) and R^(2b) are each independently    methyl or hydrogen; R^(3a) and R^(3b) are each independently    hydrogen or (C₁-C₂)alkyl (preferably (2R)-methyl or (2R)-ethyl); and    R⁴ is hydrogen or (C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug    of the compound or the nitrogen oxide; a pharmaceutically acceptable    salt of the compound, the nitrogen oxide, or the prodrug, or a    solvate or hydrate of the compound, the nitrogen oxide, the prodrug,    or the salt.

When Z is N, then X is preferably CH; Y is CR, where R for eachoccurrence is hydrogen or methyl; (i) R^(1a) is halogen, (C₁-C₄)alkyl,trifluoromethyl, methoxy, or trifluoromethoxy, and R^(1b), R^(1d) andR^(1e) are each hydrogen, (ii) R^(1b) is halogen, methyl, or methoxy andR^(1a), R^(1d) and R^(1e) are each hydrogen, (iii) R^(1a) and R^(1b) areeach independently halogen or methyl and R^(1d) and R^(1e) are eachhydrogen, (iv) R^(1b) and R^(1d) are each independently halogen ormethyl and R^(1a) and R^(1e) are each hydrogen, (v) R^(1a) and R^(1d)are each independently halogen or methyl and R^(1b) and R^(1e) are eachhydrogen,

-   -   (vi) R^(1a) and R^(1e) are each independently halogen or methyl        and R^(1b) and R^(1d) are each hydrogen, or (vii) R^(1a), R^(1b)        and R^(1d) are each independently halogen or methyl and R^(1e)        is hydrogen; W is oxy or amino; n is 1; R^(2a) and R^(2b) are        each independently methyl or hydrogen; and R^(3a) is hydrogen,        (2R)-methyl, or (2R)-ethyl; and R^(3b) is hydrogen; and R⁴ is        hydrogen or (C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of        the compound or the nitrogen oxide; a pharmaceutically        acceptable salt of the compound, the nitrogen oxide, or the        prodrug, or a solvate or hydrate of the compound, the nitrogen        oxide, the prodrug, or the salt.

When X is N, then Y is preferably CR, where R is hydrogen or methyl; Zis CH; (i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl, methoxy ortrifluoromethoxy and R^(1b), R^(1d) and R^(1e) are each hydrogen; (ii)R^(1b) is halogen, methyl, or methoxy and R^(1a), R^(1d) and R^(1e) areeach hydrogen, (iii) R^(1b) and R^(1d) are each independently halogen ormethyl and R^(1a) and R^(1e) are each hydrogen, or (iv) R^(1a) andR^(1d) are each independently halogen or methyl and R^(1b) and R^(1e)are each hydrogen; W is amino; n is 1; R^(2a) and R^(2b) are eachindependently methyl or hydrogen; R^(3a) is hydrogen, (2R)-methyl, or(2R)-ethyl; and R^(3b) is hydrogen; and R⁴ is hydrogen or (C₁-C₄)alkyl;a nitrogen oxide thereof, a prodrug of the compound or the nitrogenoxide; a pharmaceutically acceptable salt of the compound, the nitrogenoxide, or the prodrug, or a solvate or hydrate of the compound, thenitrogen oxide, the prodrug, or the salt.

Non-limiting examples of preferred compounds of Formula (IA) include;

-   -   2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   (3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   (3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,    -   2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,    -   2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and    -   4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine,    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Preferred salts include2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,hydrochloride;(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,hydrochloride;(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate;2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;and 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride.

Non-limiting examples of more preferred compounds of Formula (IA)include;

-   -   2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   (3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   (3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and    -   4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine;    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

In yet another embodiment of the present invention, compounds of Formula(IC) are provided.

wherein

-   -   X and Y are CR and Z is N, or X is N and Y and Z are CR, where R        for each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino,        or (C₁-C₄)alkylamino;    -   W is oxy, thio, amino, (C₁-C₄)alkylamino, or acetylamino;    -   Q is a heteroaryl group selected from the group consisting of        pyridin-2-yl, pyridin-3-yl, furan-3-yl, furan-2-yl,        thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, pyrrol-2-yl,        pyrrol-3-yl, pyrazol-3-yl, quinolin-2-yl, quinolin-3-yl,        isoquinolin-3-yl, benzofuran-2-yl, benzofuran-3-yl,        isobenzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl,        indol-2-yl, indol-3-yl, 2H-imidazol-2-yl, oxazol-2-yl,        isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-triazol-3-yl, and        1,2,4-oxathiazol-3-yl, where said heteroaryl group is optionally        substituted with one to three substituents independently        selected from halo, (C₁-C₄)alkyl or (C₁-C₄)alkyoxy;    -   R^(2a) and R^(2b) are each independently hydrogen, (C₁-C₄)alkyl,        or partially or fully saturated (C₃-C₆)cycloalkyl;    -   R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,        or (C₁-C₄)alkyl substituted with hydroxy, fluoro, or        (C₁-C₄)alkoxy;    -   R⁴ is hydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted        with hydroxy or cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxy-carbonyl, (C₃-C₄)alkenyl, or an amino-protecting        group;    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Non-limiting examples of preferred compounds of Formula (IC) include:4-piperazin-1-yl-2-(pyridin-2-ylmethoxy)-pyrimidine,2-(6-methyl-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine, and2-(6-chloro-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine; a nitrogenoxide thereof, a prodrug of the compound or the nitrogen oxide; apharmaceutically acceptable salt of the compound, the nitrogen oxide, orthe prodrug, or a solvate or hydrate of the compound, the nitrogenoxide, the prodrug, or the salt.

Non-limiting examples of more preferred compounds of Formula (IC)include 2-(6-methyl-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine and2-(6-chloro-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine; a nitrogenoxide thereof, a prodrug of the compound or the nitrogen oxide; apharmaceutically acceptable salt of the compound, the nitrogen oxide, orthe prodrug, or a solvate or hydrate of the compound, the nitrogenoxide, the prodrug, or the salt.

Some of the compounds described herein contain at least one chiralcenter; consequently, those skilled in the art will appreciate that allstereoisomers (e.g., enantiomers and diasteroisomers) of the compoundsillustrated and discussed herein are within the scope of the presentinvention. In addition, tautomeric forms of the compounds are alsowithin the scope of the present invention.

In another embodiment of the present invention, a pharmaceuticalcomposition is provided that comprises (1) a compound of Formula (IA) or(IC), a nitrogen oxide thereof, a prodrug of the compound or thenitrogen oxide; a pharmaceutically acceptable salt of the compound, thenitrogen oxide, or the prodrug, or a solvate or hydrate of the compound,the nitrogen oxide, the prodrug, or the salt, and (2) a pharmaceuticallyacceptable excipient, diluent, or carrier.

In yet another embodiment of the present invention, a method fortreating 5-HT₂ (preferably, 5-HT_(2c)) receptor-mediated diseases,conditions, or disorders in an animal that includes the step ofadministering to the animal a therapeutically effective amount of acompound of Formula (IB)

wherein

-   -   X and Y are CR and Z is N, or X is N and Y and Z are CR, where R        for each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino,        or (C₁-C₄)alkylamino;    -   W is oxy, thio, amino, (C₁-C₄)alkylamino, or acetylamino;    -   R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are each independently        hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,        halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted        (C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a        five- or six-membered, aromatic or partially or fully saturated        fused ring, or R^(1a) taken together with R^(2a) or R^(2b) forms        a five- or six-membered, fully saturated, fused ring;    -   R^(2a) and R^(2b) are each independently hydrogen, (C₁-C₄)alkyl,        partially or fully saturated (C₃-C₆)cycloalkyl, or one of which        taken together with R^(1a) forms a five- or six-membered, fully        saturated fused ring;    -   n is 0, 1, or 2;    -   R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,        (C₁-C₄)alkyl substituted with hydroxy, fluoro, or (C₁-C₄)alkoxy;    -   R⁴ is hydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted        with hydroxy or cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxy-carbonyl, or (C₃-C₄)alkenyl;    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt. Alternatively, compounds having Formula (IC) above may        also be used as the therapeutic agent.

Non-limiting examples of preferred compounds of Formula (IB) include2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,

-   -   2-benzyloxy-4-piperazin-1-yl-pyrimidine,    -   4-benzyloxy-2-piperazin-1-yl-pyrimidine,    -   benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   (3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   (3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   2-[1-(3-fluoro-phenyl)-ethoxy]-4-methyl-6-piperazin-1-yl-pyrimidine,    -   2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,    -   2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,    -   2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and    -   4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine;        a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Non-limiting examples of more preferred compounds include

-   -   2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,    -   benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   benzyl-(4-piperazi n-1-yl-pyrimidin-2-yl)-amine,    -   4-benzyloxy-2-piperazin-1-yl-pyrimidine,    -   2-benzyloxy-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   (3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   (3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,    -   (3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,    -   2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,    -   2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,    -   2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and    -   4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine;        a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Compounds of the present invention may be administered in combinationwith other pharmaceutical agents, such as apo-B/MTP inhibitors, MCR-4agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimeticagents, β₃ adrenergic receptor agonists, dopamine agonists,melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptorantagonists, melanin concentrating hormone antagonists, leptins, leptinanalogs, leptin receptor agonists, galanin antagonists, lipaseinhibitors, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone or analogs thereof, glucocorticoidreceptor agonists or antagonists, orexin receptor antagonists, urocortinbinding protein antagonists, glucagon-like peptide-1 receptor agonists,ciliary neurotrophic factors, AGRPs (human agouti-related proteins),ghrelin receptor antagonists, histamine 3 receptor antagonists orreverse agonists, neuromedin U receptor agonists, and the like.

The combination therapy may be administered as (a) a singlepharmaceutical composition which comprises a compound of the presentinvention, at least one additional pharmaceutical agent described aboveand a pharmaceutically acceptable excipient, diluent, or carrier; or (b)two separate pharmaceutical compositions comprising (i) a firstcomposition comprising a compound of Formula (IA), (IC), or (IB) and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent described above and a pharmaceutically acceptable excipient,diluent, or carrier. The pharmaceutical compositions may be administeredsimultaneously or sequentially and in any order.

In yet another aspect of the present invention, a pharmaceutical kit isprovided for use by a consumer to treat or prevent 5-HT₂receptor-mediated diseases, conditions, or disorders in an animal(preferably, 5-HT_(2c) receptor-mediated diseases, conditions ordisorders). The kit comprises a) a suitable dosage form comprising acompound of the present invention; and b) instructions describing amethod of using the dosage form to treat or prevent a 5-HT₂receptor-mediated disease, condition, or disorder.

In yet another embodiment of the present invention is a pharmaceuticalkit comprising: a) a first dosage form comprising (i) a compound of thepresent invention and (ii) a pharmaceutically acceptable carrier,excipient or diluent; b) a second dosage form comprising (i) anadditional pharmaceutical agent described above, and (ii) apharmaceutically acceptable carrier, excipient or diluent; and c) acontainer.

Another aspect of the present invention is a method for treating femalesexual dysfunction (FSD) comprising the step of administering to afemale in need thereof a therapeutically effective amount of a compoundof the present invention. The method may further include theadministration of one or more additional active agents for treating FSD.The additional active agents may be selected from the group consistingof (1) as estrogen receptor modulators, estrogen agonists, estrogenantagonists or combinations thereof; (2) testosterone replacement agent,testosternone (Tostrelle), dihydrotestosterone, dehydroepiandrosterone(DHEA), a testosterone implant, or combinations thereof; (3) estrogen, acombination of estrogen and medroxyprogesterone or medroxyprogesteroneacetate (MPA), or estrogen and methyl testosterone hormone replacementtherapy agent; (4) one or more dopaminergic agents; (5) one or more ofan NPY (neuropeptide Y) inhibitor; (6) one or more of a melanocortinreceptor agonist or modulator or melanocortin enhancer; (7) one or moreof an NEP inhibitor; (8) one or more of a PDE inhibitor; and (9) one ormore of a bombesin receptor antagonist or modulator. The FSD treatmentsinclude female sexual arousal disorder (FSAD), female orgasmic disorder(FOD), hypoactive sexual desire disorder (HSDD), or sexual paindisorder.

In another embodiment of the present invention, a method is provided fortreating male erectile dysfunction (MED) comprising the step ofadministering to a male in need thereof a therapeutically effectiveamount of a compound of the present invention.

Another aspect of the present invention is a method of increasing leanmeat content in an edible animal comprising the step of administering tothe edible animal a lean meat increasing amount of a compound of thepresent invention or a composition comprising the compound of thepresent invention. The compounds of the present invention may also beadministered to the edible animal in combination with any one of theadditional pharmaceutical agents described above.

Definitions

As used herein, the term “alkyl” refers to a hydrocarbon radical of thegeneral formula C_(n)H_(2n+1). The alkane radical may be straight orbranched. For example, the term “(C₁-C₄)alkyl” refers to a monovalent,straight, or branched aliphatic group containing 1 to 4 carbon atoms(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, and other constitutional isomers containing 1 to 4 carbon atoms(including stereoisomers). The alkane radical may be unsubstituted orsubstituted with one or more substituents. For example, a“halo-substituted alkyl” refers to an alkyl group substituted with oneor more halogen atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, perfluoroethyl, chloromethyl, bromomethyl, and thelike). Similarly, the alkyl portion of an alkoxy, alkylamino,dialkylamino, or alkylthio group has the same meaning as alkyl definedabove and the halo-substituted alkyl portion of a halo-substitutedalkoxy, alkyl amino, dialkylamino or alkylthio group has the samemeaning as halo-substituted alkyl defined above.

The term “partially or fully saturated cycloalkyl” refers to nonaromaticrings that are either partially or fully hydrogenated. For example,partially or fully saturated (C₃-C₆)cycloalkyl includes groups such ascyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,cycipentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and the like. Unless specified otherwise, the term“fused ring” refers to partially or fully saturated as well as aromaticcarbocyclic and heterocyclic ring systems. Preferably, the heterocyclicring contains 1 or 2 heteroatoms independently selected from nitrogen,oxygen, and sulfur (optionally oxidized to the corresponding sulfone orsulfoxide). Non-limiting examples of fused ring systems includenaphthalene, indane, indene, isoindene, benzofuran, isobenzofuran,benzo[b]thiophene, benzo[c]thiophene, indole, 3H-indole, 1H-isoindole,indazole, indoxazine, benzoxazole, anthranil, tetralin, 2H-1-benzopyran,quinoline, isoquinoline, cinnoline, quinazoline, 2H-1,3-benzoxazine,2H-1,4-benzoxazine, 1H-2,3-benzoxazine, 4H-2,1-benzoxazine,2H-1,2-benzoxazine, 4H-1,4-benzoxazine, and the like.

The term “heteroaryl” refers to aromatic monocyclic or bicyclic ringsystems containing 1, 2 or 3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. The heteroaryl group may be unsubstitutedor substituted with 1 to 3 substituents. Preferred substituents includehalo (Br, Cl, I, or F), (C₁-C₄) alkyl, and (C₁-C₄) alkoxy. Suitableheteroaryl groups include pyridin-2-yl, pyridin-3-yl, furan-3-yl,furan-2-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, pyrrol-2-yl,pyrrol-3-yl, pyrazol-3-yl, quinolin-2-yl, quinolin-3-yl,isoquinolin-3-yl, benzofuran-2-yl, benzofuran-3-yl, isobenzofuran-3-yl,benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl, indol-3-yl,2H-imidazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl,1,2,4-triazol-3-yl, 1,2,4-oxathiazol-3-yl, and the like.

The term “substituted” means that a hydrogen atom on a molecule has beenreplaced with a different atom or molecule. The atom or moleculereplacing the hydrogen atom is denoted as a “substituent.” The termsubstituted specifically envisions and allows for substitutions that arecommon in the art. However, it is generally understood by those skilledin the art that the substituents should be selected so as to notadversely affect the pharmacological characteristics of the compound oradversely interfere with the use of the medicament.

The term “nitrogen oxide” or “N-oxide” refers to the oxidation of atleast one of the nitrogens in the pyrimidine or pyrazine ring of thecompounds of Formula (IA), (IB) or (IC)(e.g., mono- or di-oxide). Thenitrogen mono-oxides may exist as a single positional isomer or amixture of positional isomers (e.g., a mixture of 1-N-oxide and3-N-oxide pyrimidines or a mixture of 1-N-oxide and 4-N-oxidepyrazines).

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The term “ligand” refers to a compound that binds to a receptor. As usedherein, the ligand may possess partial or full agonist or antagonistactivity.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “animal” refers to humans, companion animals (e.g., dogs, catsand horses), food-source animals, zoo animals, marine animals, birds andother similar animal species. “Edible animals” refers to food-sourceanimals such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formulae (IA), (IC) and(IB), nitrogen oxides thereof, prodrugs of the compounds or nitrogenoxides, pharmaceutically acceptable salts of the compounds, nitrogenoxides, and/or prodrugs, and hydrates or solvates of the compounds,nitrogen oxides, salts, and/or prodrugs, as well as, all stereoisomers(including diastereoisomers and enantiomers), tautomers and isotopicallylabeled compounds.

DETAILED DESCRIPTION

The present invention provides a method for treating or preventing 5-HT₂receptor-mediated diseases, conditions, or disorders by administeringcompounds of Formula (IB) which act as 5-HT₂ receptor ligands(preferably, 5-HT_(2c) and/or 5-HT_(2a) receptor ligands).

wherein

-   -   X and Y are CR and Z is N, or X is N and Y and Z are CR, where R        for each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino,        or (C₁-C₄)alkylamino;    -   W is oxy, thio, amino, (C₁-C₄)alkylamino, or acetylamino;    -   R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are each independently        hydrogen, halogen, nitro, cyano, amino, —C(O)NH₂, (C₁-C₄)alkyl,        halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted        (C₁-C₄)alkoxy, R^(1a) and R^(1b) taken together form a five- or        six-membered, aromatic or partially or fully saturated fused        ring, or R^(1a) taken together with R^(2a) or R^(2b) forms a        five- or six-membered, fully saturated fused ring;    -   R^(2a) and R^(2b) are each independently hydrogen, (C₁-C₄)alkyl,        partially or fully saturated (C₃-C₆)cycloalkyl, or one of which        taken together with R^(1a) forms a five- or six-membered, fully        saturated fused ring;    -   n is 0, 1, or 2 (preferably 1 or 2);    -   R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,        or (C₁-C₄)alkyl substituted with hydroxy, fluoro, or        (C₁-C₄)alkoxy;    -   R⁴ is hydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted        with hydroxy or cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy,        (C₁-C₆)alkoxy-carbonyl, or (C₃-C₄)alkenyl;    -   a nitrogen oxide thereof, a prodrug of the compound or the        nitrogen oxide; a pharmaceutically acceptable salt of the        compound, the nitrogen oxide, or the prodrug, or a solvate or        hydrate of the compound, the nitrogen oxide, the prodrug, or the        salt.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those known in the chemicalarts, particularly in light of the description contained herein. Thestarting materials are generally available from commercial sources suchas Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section. Those skilled inthe art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art. For example, a sulfide linkage (i.e.,W═S) can be easily oxidized to its corresponding sulfinyl or sulfonylgroup (i.e., W═SO or SO₂) using common oxidation procedures (e.g.,oxidation with m-chloroperbenzoic acid).

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups (NH-Pg) includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protectionis readily determined by one skilled in the art. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

Scheme I illustrates the preparation of compounds of the presentinvention where W is O, S, amino or (C₁-C₄)alkylamino.

Reaction of the di-halogen substituted heteroaryl compound of Formula IIwith a compound of Formula III (R⁴ may optionally be an amino-protectinggroup) in a suitable solvent (e.g., ethanol, t-butanol, n-butanol,toluene, dioxane, THF, DMF, or acetonitrile) in the presence of asuitable base (e.g., sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide (NaOH), potassium hydroxide,1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), triethylamine (TEA) orpyridine) at about 25° C. to about 200° C. for about 1 to about 168hours gives intermediate IV. Treatment of intermediate IV with an excessof the appropriate amine in a solvent (e.g., EtOH, t-BuOH, dioxane, THFor DMF) in the presence of a suitable base (e.g., sodium carbonate,potassium carbonate, cesium carbonate, NaOH, sodium hydride, DBU, TEA orpyridine) at about 25° C. to about 200° C. for about 1 to about 7 daysproduces intermediate V wherein W is an amino linking group or a(C₁-C₄)alkyl substituted amino linking group. Suitable amines includebenzylamine, 3-chlorobenzyl amine, 3-fluorobenzyl amine, and the like.

Alternatively, intermediate IV may be reacted with an anion of anappropriate alcohol or thiol in a solvent (e.g., THF, toluene, dioxane,DMF, benzene, or a mixture of benzene and water) with or without acatalyst such as 18-crown-6 at about 25° C. to about 200° C. for about 1to about 48 hours to yield compounds of formula V wherein W is O or S.The anion may be obtained by treatment of the corresponding alcohol orthiol with a base (e.g., potassium carbonate, sodium hydride, sodiumhydroxide, potassium hydroxide, potassium t-butoxide, or sodium metal)in an inert solvent (e.g., toluene, dioxane, DMF, THF, or benzene) atabout 25° C. to about 200° C. for about 1 to about 24 hours.

Suitable alcohols include benzyl alcohol, α-phenethyl alcohol,β-phenethyl alcohol, 3-fluoro-benzyl alcohol, 3-chloro-benzyl alcohol,3-methoxybenzyl alcohol, 2-chlorobenzyl alcohol, 3-fluoro-α-phenethylalcohol, 2-chloro-α-phenethyl alcohol, 3-chloro-α-phenethyl alcohol,2,5-difluorobenzyl alcohol, 2,5-dichlorobenzyl alcohol,3,5-difluorobenzyl alcohol, 3,5-dichlorobenzyl alcohol,2-hydroxymethylpyridine, 2-hydroxymethyl-6-chloro-pyridine,2-hydroxymethyl-6-methyl-pyridine, and the like.

Suitable thiols include, α-toluenethiol, (2-methylphenyl)methanethiol,3-(trifluoromethyl)-α-toluenethiol, 2-chloro-α-toluenethiol,(3-methylphenyl)-methanethiol, 2-chloro-6-fluorobenzylmercaptan,o-fluorobenzyl mercaptan, m-chlorobenzyl mercaptan,2,4,6-trimethylbenzyl mercaptan, and the like.

The sulfide linkage can be oxidized to the corresponding sulfinyl orsulfonyl using standard oxidation procedures well known to those skilledin the art.

When R⁴ is an amino-protecting group, intermediate V is deprotected togive the amine VI. For example, a BOC protected amine may be deprotectedby treatment with trifluoroacetic acid (TFA) in CH₂Cl₂. The secondaryamine VI can then be alkylated to the amine VII by methods well known tothose skilled in the art. A preferred method is reductive alkylation.Generally, reductive alkylation reactions convert intermediate VI into aSchiff base by reaction with the desired aldehyde or ketone in a polarsolvent at a temperature from about 10° C. to about 140° C. for about 2to about 24 hours in the presence of 3 Å molecular sieves. Typically, anequivalent or a slight excess of the aldehyde or ketone is added to theamine. Suitable polar solvents include methylene chloride,1,2-dichloroethane, dimethylsulfoxide, dimethylformamide, alcohols(e.g., methanol or ethanol), or mixtures thereof. A preferred solvent ismethanol. In the same reaction vessel, the imine is then reduced to thetertiary amine in the presence of a reducing agent at a temperature fromabout 0° C. to about 10° C. and then warmed to a temperature from about20° C. to about 40° C. for about 30 minutes to about 2 hours. Suitablereducing agents include pyridine borane complex and metal borohydrides,such as sodium borohydride, sodium triacetoxy borohydride and sodiumcyanoborohydride. Suitable aldehydes or ketones includeparaformaldehyde, acetaldehyde, acetone and the like.

Alternatively, the amine VI may be acylated or converted to a carbamateaccording to methods well known to those skilled in the art.

Compounds of the present invention where W is an amino linking group(NH) or alkylamino linking group can also be prepared by reductivealkylation of an amino group attached to the pyrimidine or pyrazine ringas illustrated in Scheme II below. The synthetic procedures areanalogous to those described above for the reductive alkylation ofintermediate VI in Scheme I.

The compound of Formula VIII can be converted to the benzyl amine XI bymethods well known in the art. A preferred method is reductivealkylation as described earlier in Scheme I where a Schiff base isformed with intermediate 1× and then reduced with an appropriatereducing agent. Suitable aldehydes and ketones (i.e., compound ofFormula IX) include 3-chlorobenzaldehyde, 3-fluorobenzaldehyde,m-chloroacetophenone, m-chloropropiophenone, o-chloroacetophenorie,2-fluorobenzaldehyde, 2-chlorobenzaldehyde, 2,6-d ichlorobenzaldehyde,2,5-d ichloroacetophenone, 2-chloro-5-methylacetophenone,2,5-difluoroacetophenone, 2,5-difluoropropiophenone,2,3-dichlorobenzaldehyde, 2,3-difluorobenzaldehyde,2,5-difluorobenzaldehyde, 2-chloro-5-fluoroacetophenone,5-chloro-2-methoxybenzaldehyde, 2-fluoro-5-methoxybenzaldehyde,2,5-dichlorobenzaldehyde, 3,5-dichlorobenzaldehyde,3,5-dichloroacetophenone, 3,5-difluorobenzaldehyde,2,3,5-trifluorobenzaldehyde, 2,3,5-trifluoroacetophenone,2,3,5-trifluoropropiophenone, 2,3,5-trichlorobenzaldehyde,2,3,6-trifluorobenzaldehyde, and the like. Treatment of the resultantcompound of Formula X with piperazine III in a suitable solvent (e.g.,ethanol, t-butanol, n-butanol, toluene, dioxane, THF, DMF oracetonitrile) in the presence of a suitable base (e.g., sodiumcarbonate, potassium carbonate, sodium hydroxide, TEA, DBU or pyridine)at about 25⁰ to about 200° C. for about 1 day to about seven days givescompounds of the Formula XI.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of the present invention, as well as the various intermediatesrelated thereto. Such techniques will be well-known to one of ordinaryskill in the art and may include, for example, all types ofchromatography (high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography), recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

The compounds of the present invention may be isolated and used per seor in the form of its pharmaceutically acceptable salt, solvate and/orhydrate. The term “salts” refers to inorganic and organic salts of acompound of the present invention. These salts can be prepared in situduring the final isolation and purification of a compound, or byseparately reacting the compound, N-oxide, or prodrug with a suitableorganic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride,hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate,oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate,malate, borate, benzoate, lactate, phosphate, hexafluorophosphate,benzene sulfonate, tosylate, formate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

The term “nitrogen oxide” or “N-oxide” refers to the oxidation of atleast one of the nitrogen atoms in the pyrimidine or pyrazine ring.Oxidation of aromatic nitrogens is well known in the art. Typicaloxidizing agents include reagents such as hydrogen peroxide,trifluoroperacetic acid, m-chloroperbenzoic acid and the like. Ingeneral, the oxidation is accomplished in an inert solvent (e.g.,methylene chloride or chloroform). The position of the N-oxidation mayvary depending upon the steric hinderance from substituents on anadjacent carbon atom. The N-oxide or mixture of N-oxides can be isolatedor separated using conventional procedures such as liquid chromatographyand/or selective crystallization.

The term “prodrug” means a compound that is transformed in vivo to yielda compound of Formula (IA, IB or IC) or a pharmaceutically acceptablesalt, hydrate or solvate of the compound. The transformation may occurby various mechanisms, such as through hydrolysis in blood. A discussionof the use of prodrugs is provided by T. Higuchi and W. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of the present invention contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the present invention incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY′ wherein Y′ is H,(C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄) alkyl and Y₁ is(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃ wherein Y₂ is H or methyl and Y₃is mono-N- or di-N,N-(C₁-C₆)alkylamino, morpholino, piperidin-1-yl orpyrrolidin-1-yl.

The compounds of the present invention may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of the presentinvention as well as mixtures thereof, including racemic mixtures, formpart of the present invention. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the present invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Both the single positional isomersand mixture of positional isomers resulting from the N-oxidation of thepyrimidine and pyrazine rings are also within the scope of the presentinvention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

It is also possible that the compounds of the present invention mayexist in different tautomeric forms, and all such forms are embracedwithin the scope of the invention. For example, all of the tautomericforms of the imidazole moiety are included in the invention. Also, forexample, all keto-enol and imine-enamine forms of the compounds areincluded in the invention.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively.

Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Compounds of the present invention are useful 5-HT₂ partial agonists orantagonists (preferably 5-HT_(2a) or 5-HT_(2c) partial agonists orantagonists); therefore, another embodiment of the present invention isa pharmaceutical composition comprising a therapeutically effectiveamount of a compound of the present invention and a pharmaceuticallyacceptable excipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wefting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The compound of the presentinvention is typically formulated into pharmaceutical dosage forms toprovide an easily controllable dosage of the drug and to give thepatient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present invention further provides methods of treating 5-HT₂receptor-mediated diseases, conditions, or disorders in an animal inneed of such treatment that include administering to the animal atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition comprising an effective amount of acompound of the present invention and a pharmaceutically acceptableexcipient, diluent, or carrier. The method is particularly useful fortreating 5-HT_(2c) receptor-mediated diseases, conditions, or disorders.Preferably, the compounds of the present invention act as a partialagonist at the 5-HT_(2c) receptor site. More preferably, the compoundsof the present invention act as a partial agonist the 5-HT_(2c) receptorsite and as an antagonist at the 5-HT_(2a) receptor site.

Preferably, the 5-HT₂ receptor-mediated disease, condition, or disorderis selected from the group consisting of weight loss (e.g., reduction incalorie intake), obesity, bulimia, premenstrual syndrome or late lutealphase syndrome, depression, atypical depression, bipolar disorders,psychoses, schizophrenia, migraine, alcoholism, tobacco abuse, panicdisorder, anxiety, post-traumatic syndrome, memory loss, dementia ofaging, social phobia, attention deficit hyperactivity disorder,disruptive behavior disorders, impulse control disorders, borderlinepersonality disorder, obsessive compulsive disorder, chronic fatiguesyndrome, sexual dysfunction in males (e.g., premature ejaculation anderectile difficulty), sexual dysfunction in females, anorexia nervosa,disorders of sleep (e.g., sleep apnea), autism, seizure disorders,epilepsy, mutism, spinal cord injury, damage of the central nervoussystem (e.g., trauma, stroke, neurodegenerative diseases or toxic orinfective CNS diseases (e.g., encephalitis or meningitis)),cardiovascular disorders (e.g., thrombosis), gastrointestinal disorders(e.g., dysfunction of gastrointestinal motility), diabetes insipidus,and type II diabetes. Accordingly, the compounds of the presentinvention described herein are useful in treating 5-HT₂receptor-mediated diseases, conditions, or disorders. Consequently, thecompounds of the present invention (including the compositions andprocesses used therein) may be used in the manufacture of a medicamentfor the therapeutic applications described herein

The compounds of the present invention can be administered to a patientat dosage levels in the range of from about 0.7 mg to about 7,000 mg perday. For a normal adult human having a body weight of about 70 kg, adosage in the range of from about 0.01 mg to about 100 mg per kilogrambody weight is typically sufficient. However, some variability in thegeneral dosage range may be required depending upon the age and weightof the subject being treated, the intended route of administration, theparticular compound being administered and the like. The determinationof dosage ranges and optimal dosages for a particular patient is wellwithin the ability of one of ordinary skill in the art having thebenefit of the instant disclosure. It is also noted that the compoundsof the present invention can be used in sustained release, controlledrelease, and delayed release formulations, which forms are also wellknown to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases/conditionsdescribed herein. Therefore, methods of treatment that includeadministering compounds of the present invention in combination withother pharmaceutical agents are also provided. Suitable pharmaceuticalagents that may be used in combination with the compounds of the presentinvention include anti-obesity agents such as apolipoprotein-Bsecretion/microsomal triglyceride transfer protein (apo-B/MTP)inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists,monoamine reuptake inhibitors (such as sibutramine), sympathomimeticagents, β₃ adrenergic receptor agonists, dopamine agonists (such asbromocriptine), melanocyte-stimulating hormone receptor analogs,cannabinoid 1 receptor antagonists, melanin concentrating hormoneantagonists, leptins (the OB protein), leptin analogs, leptin receptoragonists, galanin antagonists, lipase inhibitors (such astetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents,dehydroepiandrosterone or an analog thereof, glucocorticoid receptoragonists or antagonists, orexin receptor antagonists, urocortin bindingprotein antagonists, glucagon-like peptide-1 receptor agonists, ciliaryneurotrophic factors (such as Axokine™ available from RegeneronPharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company,Cincinnati, Ohio), human agouti-related proteins (AGRP), ghrelinreceptor antagonists, histamine 3 receptor antagonists or reverseagonists, and neuromedin U receptor agonists. Other anti-obesity agents,including the preferred agents set forth hereinbelow, are well known, orwill be readily apparent in light of the instant disclosure, to one ofordinary skill in the art.

Especially preferred are anti-obesity agents selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,and pseudoephedrine. Preferably, compounds of the present invention andcombination therapies are administered in conjunction with exercise anda sensible diet.

Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, sibutramine can be prepared as described in U.S. Pat. No.4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos.3,752,814 and 3,752,888; and orlistat can be prepared as described inU.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. All ofthe above recited U.S. patents are incorporated herein by reference.

The dosage of the additional pharmaceutical agent (e.g., anti-obesityagent) will also be generally dependent upon a number of factorsincluding the health of the subject being treated, the extent oftreatment desired, the nature and kind of concurrent therapy, if any,and the frequency of treatment and the nature of the effect desired. Ingeneral, the dosage range of an anti-obesity agent is in the range offrom about 0.001 mg to about 100 mg per kilogram body weight of theindividual per day, preferably from about 0.1 mg to about 10 mg perkilogram body weight of the individual per day. However, somevariability in the general dosage range may also be required dependingupon the age and weight of the subject being treated, the intended routeof administration, the particular anti-obesity agent being administeredand the like. The determination of dosage ranges and optimal dosages fora particular patient is also well within the ability of one of ordinaryskill in the art having the benefit of the instant disclosure.

In another embodiment of the present invention, the compounds of thepresent invention are useful in the treatment of sexual dysfunction.Sexual dysfunction (SD) is a significant clinical problem, which canaffect both males and females. The causes of SD may be both organic aswell as psychological. Organic aspects of SD are typically caused byunderlying vascular diseases, such as those associated with hypertensionor diabetes mellitus, by prescription medication and/or by psychiatricdisease such as depression. Physiological factors include fear,performance anxiety and interpersonal conflict. SD impairs sexualperformance, diminishes self-esteem and disrupts personal relationshipsthereby inducing personal distress. In the clinic, SD disorders havebeen divided into female sexual dysfunction (FSD) disorders and malesexual dysfunction (MSD) disorders (Melman et al 1999). FSD is bestdefined as the difficulty or inability of a woman to find satisfactionin sexual expression. Male sexual dysfunction (MSD) is generallyassociated with erectile dysfunction, also known as male erectiledysfunction (MED) (Benet et al 1994—Male Erectile dysfunction assessmentand treatment options. Comp. Ther. 20: 669-673.).

The compounds of the invention are particularly beneficial for theprophylaxis and/or treatment of sexual dysfunction in the male (e.g.male erectile dysfunction—MED) and in the female—female sexualdysfunction (FSD), e.g. female sexual arousal disorder (FSAD).

It is known that some individuals can suffer from male erectiledysfunction (MED). MED is defined as: “the inability to achieve and/ormaintain a penile erection for satisfactory sexual performance” (NIHConsensus Development Panel on Impotence, 1993)”

It has been estimated that the prevalence of erectile dysfunction (ED)of all degrees (minimal, moderate and complete impotence) is 52% in men40 to 70 years old, with higher rates in those older than 70 (Melman, A.& Gingell, J. C. (1999). The epidemiology and pathophysiology oferectile dysfunction. J. Urology 161: 5-11). The condition has asignificant negative impact on the quality of life of the patient andtheir partner, often resulting in increased anxiety and tension whichleads to depression and low self esteem. Whereas two decades ago, MEDwas primarily considered to be a psychological disorder (Benet, A. E. etal (1994), Male erectile dysfunction assessment and treatment options.Comp. Ther. 20: 669-673), it is now known that for the majority ofpatients there is an underlying organic cause. As a result, muchprogress has been made in identifying the mechanism of normal penileerection and the pathophysiology of MED.

Penile erection is a haemodynamic event which is dependent upon thebalance of contraction and relaxation of the corpus cavernosal smoothmuscle and vasculature of the penis (Lerner, S. E. et al (1993). Areview of erectile dysfunction: new insights and more questions. J.Urology 149: 1246-1255). Corpus cavernosal smooth muscle is alsoreferred to herein as corporal smooth muscle or in the plural sensecorpus cavernosa. Relaxation of the corpus cavernosal smooth muscleleads to an increased blood flow into the trabecular spaces of thecorpus cavernosa, causing them to expand against the surrounding tunicaand compress the draining veins. This produces a vast elevation in bloodpressure which results in an erection (Naylor, A. M. (1998). Endogenousneurotransmitters mediating penile erection. Br. J. Urology 81:424-431).

The changes that occur during the erectile process are complex andrequire a high degree of coordinated control involving the peripheraland central nervous systems, and the endocrine system (Naylor, 1998).Corporal smooth muscle contraction is modulated by sympatheticnoradrenergic innervation via activation of postsynaptic α₁adrenoceptors. MED may be associated with an increase in the endogenoussmooth muscle tone of the corpus cavernosum. However, the process ofcorporal smooth muscle relaxation is mediated partly by non-adrenergic,non-cholinergic (NANC) neurotransmission. There are a number of otherNANC neurotransmitters found in the penis, other than NO, such ascalcitonin gene related peptide (CGRP) and vasoactive intestinal peptide(VIP). The main relaxing factor responsible for mediating thisrelaxation is nitric oxide (NO), which is synthesized from L-arginine bynitric oxide synthase (NOS) (Taub, H. C. et al (1993). Relationshipbetween contraction and relaxation in human and rabbit corpuscavernosum. Urology 42: 698-704). It is thought that reducing corporalsmooth muscle tone may aid NO to induce relaxation of the corpuscavernosum. During sexual arousal in the male, NO is released fromneurones and the endothelium and binds to and activates solubleguanylate cyclase (sGC) located in the smooth muscle cells andendothelium, leading to an elevation in intracellular cyclic guanosine3′,5′-monophosphate (cGMP) levels. This rise in cGMP leads to arelaxation of the corpus cavernosum due to a reduction in theintracellular calcium concentration ([Ca²⁺]_(i)), via unknown mechanismsthought to involve protein kinase G activation (possibly due toactivation of Ca²⁺ pumps and Ca²⁺-activated K⁺ channels).

The categories of female sexual dysfunction (FSD) are best defined bycontrasting them to the phases of normal female sexual response: desire,arousal and orgasm (see S R Leiblum, (1998), Definition andClassification of Female Sexual Disorders, Int. J. Impotence Res., 10,S104-S106). Desire or libido is the drive for sexual expression. Itsmanifestations often include sexual thoughts either when in the companyof an interested partner or when exposed to other erotic stimuli.Arousal includes the vascular response to sexual stimulation, animportant component of which is genital engorgement and increasedvaginal lubrication, elongation of the vagina and increased genitalsensation/sensitivity and a subjective excitement response. Orgasm isthe release of sexual tension that has culminated during arousal. Hence,FSD occurs when a woman has an absent, inadequate or unsatisfactoryresponse in any one or more of these phases, usually desire, arousal ororgasm.

The American Psychiatric Association classifies female sexualdysfunction (FSD) into four classes: FSAD, hypoactive sexual desiredisorder (HSDD), female orgasmic disorder (FOD), and sexual paindisorders (e.g. dyspareunia and vaginismus) [see the AmericanPsychiatric Association's Diagnostic and Statistical Manual of MentalDisorders, 4th Edition (DSM-IV)].

DSM-IV defines the four classes as follows:

-   -   HSDD—Persistently or recurrently deficient (or absent) sexual        fantasies and desire for sexual activity. The judgment of        deficiency or absence is made by the clinician, taking into        account factors that affect functioning, such as age and the        context of the persons life.    -   FSAD—Persistent or recurrent inability to attain, or to maintain        until completion of the sexual activity, an adequate        lubrication-swelling response of sexual excitement.    -   FOD—Persistent or recurrent delay in, or absence of, orgasm        following a normal sexual excitement phase. Women exhibit wide        variability in the type or intensity of stimulation that        triggers orgasm. The diagnosis of FOD should be based on the        clinician's judgment that the woman's orgasmic capacity is less        than would be reasonable for her age, sexual experience, and the        adequacy of the sexual stimulation she receives.

Sexual Pain Disorders such as Dyspareunia and Vaginismus.Dysparenuia—Recurrent or persistent genital pain associated with sexualintercourse. Vaginismus—Recurrent or persistent involuntary spasm of themusculature of the outer third of the vagina that interferes with sexualintercourse.

HSDD is present if a woman has no or little desire to be sexual, and hasno or few sexual thoughts or fantasies. This type of FSD can be causedby low testosterone levels, due either to natural menopause or tosurgical menopause. Other causes in both pre-menopausal woman (i.e.woman who are pre-menopausal and who have not have hysterectomies) aswell as post-menopausal women include illness, medications, fatigue,depression and/or anxiety. Factors having a potential (conscious orsub-conscious) psychological impact such as relationship difficulties orreligious factors may be related to the presence of/development of HSDDin females. The Diagnostic and Statistical Manual (DSM) IV of theAmerican Psychiatric Association defines Female Sexual Arousal Disorder(FSAD) as being: “ . . . a persistent or recurrent inability to attainor to maintain until completion of the sexual activity adequatelubrication-swelling response of sexual excitement. The disturbance mustcause marked distress or interpersonal difficulty . . . ”.

The arousal response consists of vasocongestion in the pelvis, vaginallubrication and expansion and swelling of the external genitalia. Thedisturbance causes marked distress and/or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder affecting pre-, per- andpost-menopausal (±hormone replacement therapy (HRT)) women. It isassociated with concomitant disorders such as depression, cardiovasculardiseases, diabetes and urogenital (UG) disorders. The primaryconsequences of FSAD are lack of engorgement/swelling, lack oflubrication and lack of pleasurable genital sensation. The secondaryconsequences of FSAD are reduced sexual desire, pain during intercourseand difficulty in achieving an orgasm. It has recently been hypothesizedthat there is a vascular basis for at least a proportion of patientswith symptoms of FSAD (Goldstein et al., Int. J. Impot. Res., 10,S84-S90,1998) with animal data supporting this view (Park et al., Int.J. Impot. Res., 9, 27-37, 1997).

Drug candidates for treating FSAD, which are under investigation forefficacy, are primarily erectile dysfunction therapies that promotecirculation to male genitalia. They consist of two types of formulation,oral or sublingual medications (Apomorphine, Phentolamine,phosphodiesterase type 5 (PDE5) inhibitors, e.g. Sildenafil), andprostaglandin (PGE₁) that are injected or administered transurethrallyin men and topically to the genitalia in women.

The compounds of the present invention are advantageous by providing ameans for restoring a normal sexual arousal response—namely increasedgenital blood flow leading to vaginal, clitoral and labial engorgement.This will result in increased vaginal lubrication via plasmatransudation, increased vaginal compliance and increased genitalsensitivity. Hence, the present invention provides a means to restore,or potentiate, the normal sexual arousal response.

By female genitalia herein we mean: “The genital organs consist of aninternal and external group. The internal organs are situated within thepelvis and consist of ovaries, the uterine tubes, uterus and the vagina.The external organs are superficial to the urogenital diaphragm andbelow the pelvic arch. They comprise the mons pubis, the labia majoraand minora pudendi, the clitoris, the vestibule, the bulb of thevestibule, and the greater vestibular glands” (Gray's Anatomy, C. D.Clemente, 13^(th) American Edition). R. J. Levin teaches us that because“ . . . male and female genitalia develop embryologically from thecommon tissue anlagen, [that] male and female genital structures areargued to be homologues of one another. Thus the clitoris is the penilehomologue and the labia homologues of the scrotal sac. . . . ” (Levin,R. J. (1991), Exp. Clin. Endocrinol., 98, 61-69).

In summary, FSAD is characterized by inadequate genital response tosexual stimulation. The genitalia do not undergo the engorgement thatcharacterizes normal sexual arousal. The vaginal walls are poorlylubricated, so that intercourse is painful. Orgasms may be impeded.Arousal disorder can be caused by reduced oestrogen at menopause orafter childbirth and during lactation, as well as by illnesses, withvascular components such as diabetes and atherosclerosis. Other causesresult from treatment with diuretics, antihistamines, antidepressantse.g. selective serotonin reuptake inhibitors (SSRIs) or antihypertensiveagents.

FOD is the persistent or recurrent difficulty, delay in or absence ofattaining orgasm following sufficient sexual stimulation and arousal,which causes personal distress.

Sexual pain disorders (includes dyspareunia and vaginismus) arecharacterized by pain resulting from penetration and sexual activity andmay be caused by medications which reduce lubrication, endometriosis,pelvic inflammatory disease, inflammatory bowel disease or urinary tractproblems.

According to a further aspect, the present invention additionallyprovides a method for the treatment and/or prevention of male sexualdysfunction (MSD), in particular male erectile dysfunction (MED) viatreatment with a compound of the present invention as detailed hereinbefore.

According to a yet further aspect, the present invention additionallyprovides a method for the treatment and/or prevention of male sexualdysfunction via treatment with a combination of a compound of thepresent invention as defined hereinbefore and one or more compoundswhich inhibit the activity of PDE, in particular compounds which inhibitthe activity of cGMP PDE5, and/or one or more compounds which inhibitthe activity of NEP.

Men who display an insufficient response or lack of response totreatment with Viagra™ may benefit either from therapy based ontreatment with compounds of the present invention alone or viacombination therapy based on compound(s) of the present invention and acGMP PDE5i, such as for example sildenafil. Patients with mild tomoderate MED should benefit from combined treatment based on compound(s)of the present invention alone or in combination with a NEPi, andpatients with severe MED may also respond. Mild, moderate and severe MEDwill be terms known to the man skilled in the art, but guidance can befound in: The Journal of Urology, vol 151, 54-61 (January 1994).

MED patient groups, which are described in more detail in ClinicalAndrology vol 23, no.4, p773-782, and chapter 3 of the book by 1.Eardley and K. Sethia “Erectile Dysfunction—Current Investigation andManagement, published by Mosby-Wolfe, are as follows: psyhcogenic,endocrinologic, neurogenic, arteriogenic, drug-induced sexualdysfunction (lactogenic) and sexual dysfunction related to cavernosalfactors, particularly venogenic causes.

Suitable cGMP PDE5 inhibitors for the use in combination with a compoundof the present invention for the treatment of MED according to thepresent invention include: the pyrazolo [4,3-d]pyrimidin-7-onesdisclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7-onesdisclosed in published international application WO 01/27112; thepyrazolo [4,3-d]pyrimidin-7-ones disclosed in published internationalapplication WO 01/27113; the indole-1,4-diones disclosed in WO95/19978and the triazin-4-ones disclosed in published international applicationWO99/24433.

More preferred are compounds such as,5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil) also known as1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine(see EP-A-0463756);

-   -   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        also known as        1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine        (see WO 01/27113, Example 8);    -   5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (see WO 01/27112, Example 132);    -   (6R,        12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione        (IC-351, tadalafil), i.e. the compound of examples 78 and 95 of        published international application WO95/19978, as well as the        compound of examples 1,3,7 and8; and    -   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil) also known as        1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine        (i.e. the compound of examples 20, 19, 337 and 336 of published        international application WO99/24433); and pharmaceutically        acceptable salts thereof.

According to a further aspect the present invention provides acomposition for the treatment of MED comprising a compound of thepresent invention and sildenafil.

The suitability of any particular cGMP PDE5 inhibitor for use incombination with a compound of the present invention can be readilydetermined by evaluation of its potency and selectivity using literaturemethods followed by evaluation of its toxicity, absorption, metabolism,pharmacokinetics, etc in accordance with standard pharmaceuticalpractice.

Preferred cGMP PDE5 inhibitors for use herein have an IC₅₀ at less than100 nanomolar, more preferably, at less than 50 nanomolar, morepreferably still at less than 10 nanomolar. Preferably the cGMP PDE5inhibitors for use in the pharmaceutical combinations according to thepresent invention are selective for the PDE5 enzyme. Preferably theyhave a selectivity of PDE5 over PDE3 of greater than 100 more preferablygreater than 300. More preferably the PDE5 has a selectivity over bothPDE3 and PDE4 of greater than 100, more preferably greater than 300.

Selectivity ratios may readily be determined by the skilled person. IC₅₀values for the PDE3 and PDE4 enzyme may be determined using establishedliterature methodology, see S A Ballard et al, Journal of Urology, 1998,vol. 159, pages 2164-2171.

Preferred herein are NEP inhibitors wherein said NEP is EC 3.4.24.11 andmore preferably wherein said NEP inhibitor is a selective inhibitor forEC 3.4.24.11, more preferably a selective NEP inhibitor is a selectiveinhibitor for EC 3.4.24.11, which has an IC₅₀ of less than 100 nM (e.g.ompatrilat, candoxatril, candoxatrilat, sampatrilat). Suitable NEPinhibitor compounds are described in EP-A-1097719.

Particularly preferred NEPi compounds for as auxiliary agents for use inthe treatment of MED according to the present invention are thosedescribed in co-pending International Patent Application PCT/IB02/00807filed on the 18 Mar. 2002.

Especially preferred is(S)-2-[(1-{[3-(4-chlorophenyl)propyl]-carbamoyl}cyclo-pentyl)methyl]-4-methoxybutanoicacid or a pharmacuetically acceptable salt such as the sodium saltthereof as detailed at Example 22 in PCT/IB02/00807. Details for thesynthesis of this compound and the sodium salt are provided in theExperimental Section hereinafter.

According to a further aspect the present invention provides acomposition for the treatment of MED comprising a compound of thepresent invention and(S)-2-[(1-{[3-(4-chlorophenyl)propyl]carbamoyl}cyclo-pentyl)methyl]-4-methoxybutanoicacid.

According to yet a further aspect of the present invention, there isprovided use of a compound of the present invention for the treatment offemale sexual dysfunction (FSD).

According to another aspect of the present invention, there is provideduse of a compound of the present invention and one or more additionalactive agents for the treatment of female sexual dysfunction (FSD).

Preferably, the one or more additional active agents is/are selectedfrom the group consisting of:

-   -   1) estrogen receptor modulators and/or estrogen agonists and/or        estrogen antagonists;    -   2) testosterone replacement agent and/or testosternone        (Tostrelle) and/or dihydrotestosterone and/or        dehydroepiandrosterone (DHEA) and/or a testosterone implant;    -   3) estrogen, estrogen and medroxyprogesterone or        medroxyprogesterone acetate (MPA) (as a combination), or        estrogen and methyl testosterone hormone replacement therapy        agent;    -   4) one or more dopaminergic agents;    -   5) one or more of an NPY (neuropeptide Y) inhibitor;    -   6) one or more of a melanocortin receptor agonist or modulator        or melanocortin enhancer;    -   7) one or more of an NEP (neutral endopeptidase) inhibitor;    -   8) one or more of a PDE (phosphodiesterase) inhibitor; and    -   9) one or more of a bombesin receptor antagonist or modulator.

Preferably, said FSD is female sexual arousal disorder (FSAD).Alternatively, said FSD is female orgasmic disorder (FOD). In a furtheralternative, said FSD is hypoactive sexual desire disorder (HSDD). Inyet a further alternative, said FSD is a sexual pain disorder,preferably Dyspareunia or Vaginismus.

Examples of estrogen receptor modulators and/or estrogen agonists and/orestrogen antagonists, include raloxifene or lasofoxifene,(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-oland pharmaceutically acceptable salts thereof (compound (a) below), thepreparation of which is detailed in WO 96/21656.

An example of a testosterone replacement agent is dehydroandrostendione.

Examples of hormone replacement therapy agent include Premarin,Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo,Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase,Preempro, Prempak, Premique, Estratest, Estratest HS, and Tibolone.

Examples of dopaminergic agents include apomorphine or a selective D2,D3 or D2/D₃ agonist such as, pramipexole and ropirinol (as claimed inWO-0023056),L-Dopa or carbidopa, PNU95666 (as disclosed in WO-0040226).

Examples of NPY (neuropeptide Y) inhibitors include NPY1 or NPY5inhibitors, preferably NPY1 inhibitor. Preferably, said NPY inhibitors(including NPY Y1 and NPY Y5) having an IC50 of less than 100 nM, morepreferably less than 50 nM. Suitable NPY, and in particular NPY1inhibitor compounds, are described in EP-A-1097718.

Examples of a melanocortin receptor agonist or modulator or melanocortinenhancer include melanotan II, PT-14, PT-141 or compounds disclosed inWO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361,WO-00114879, WO-00113112 or WO-09954358.

Suitable NEP inhibitors are as described hereinabove.

According to a further aspect, the present invention provides acomposition for the treatment of FSD comprising a compound of thepresent invention and(S)-2-[(1-{[3-(4-chlorophenyl)propyl]carbamoyl}cyclo-pentyl)methyl]-4-methoxybutanoicacid.

Preferred PDE inhibitors include a PDE 2, 3, 4, 5, 7 or 8 inhibitor,preferably PDE2 or PDE5 inhibitor and more preferably a PDE5 inhibitor(as described hereinabove), most preferably sildenafil.

According to a further aspect, the present invention provides acomposition for the treatment of FSD comprising a compound of thepresent invention and sildenafil.

Preferred examples of one or more of bombesin receptor antagonists ormodulators would be antagonists or modulators for BB₁, including thosedescribed in PCT/GB01/05018 (filed 14 Nov. 2001) and PCT/GB00/04380(filed 17 Nov. 2000). Also preferred are bombesin BB₂, BB₃, or BB₄receptor antagonists. Preferred bombesin receptor antagonists are alsomentioned as “auxiliary agents” in PCT/IB01/02399 (filed 10 Dec. 2001).

It should be noted that a full list of possible “additional activeagents” can be found in PCT/IB01/02399 (filed 10 December 2001)- and aredescribed as “auxiliary agents” therein.

In accordance with yet another aspect of the present invention, other5-HT_(2c) receptor agonists may be used in addition to a compound of thepresent invention. Such 5-HT_(2c) receptor agonists include, but are notlimited to, those disclosed in Chaki and Nakazato—Expert Opin. Ther.Patents (2001), 11(11):1677-1692 (see especially Section 3.9-5HT_(2c) onpage 1687 and FIG. 7 on page 1686), or Isaac—Drugs of the Future (2001),26(4):383-393 (see especially FIG. 2 on page 385). For the avoidance ofdoubt, the aforementioned publications are incorporated herein byreference in their entireties.

Preferably, said 5-HT_(2c) receptor agonists are selective 5-HT_(2c)receptor agonists.

Receptor binding data or binding selectivity data may not alwayscorrelate with or reflect functional data or functional selectivitydata. For example, a compound may be a 5-HT_(2c) receptor agonist whenbinding assays are analysed, but functionally the compound may have thesame potency at other 5-HT receptors. Thus, the term “selective” as usedherein in relation to the present invention with respect to methods oftreatment for sexual dysfunction means “functionally selective”.

Thus, according to another aspect, the present invention additionallyprovides the use of 5-HT_(2c) receptor agonists, preferably selective5-HT_(2c) receptor agonists, for the treatment of FSD, preferably FSAD,FOD, HSDD or a sexual pain disorder (such as Dyspareunia or Vaginismus).

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent is administered to a subjectin need of such treatment, preferably in the form of a pharmaceuticalcomposition. In the combination aspect of the invention, the compound ofthe present invention and at least one other pharmaceutical agent (e.g.,anti-obesity agent described above) may be administered eitherseparately or in the pharmaceutical composition comprising both. It isgenerally preferred that such administration be oral. However, if thesubject being treated is unable to swallow, or oral administration isotherwise impaired or undesirable, parenteral or transdermaladministration may be appropriate.

According to the methods of the invention, when a combination of acompound of the present invention and at least one other pharmaceuticalagent are administered together, such administration can be sequentialin time or simultaneous with the simultaneous method being generallypreferred. For sequential administration, a compound of the presentinvention and the additional pharmaceutical agent can be administered inany order. It is generally preferred that such administration be oral.It is especially preferred that such administration be oral andsimultaneous. When a compound of the present invention and theadditional pharmaceutical agent are administered sequentially, theadministration of each can be by the same or by different methods.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent (referred to herein as a“combination”) is preferably administered in the form of apharmaceutical composition. Accordingly, a compound of the presentinvention or a combination can be administered to a patient separatelyor together in any conventional oral, rectal, transdermal, parenteral,(for example, intravenous, intramuscular, or subcutaneous)intracisternal, intravaginal, intraperitoneal, intravesical, local (forexample, powder, ointment or drop), or buccal, or nasal, dosage form.

Compositions suitable for parenteral injection generally includepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of microorganismcontamination of the compositions can be accomplished with variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, a compound of thepresent invention or a combination is admixed with at least one inertcustomary pharmaceutical excipient (or carrier) such as sodium citrateor dicalcium phosphate or (a) fillers or extenders (e.g., starches,lactose, sucrose, mannitol, silicic acid and the like); (b) binders(e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, acacia and the like); (c) humectants (e.g., glycerol and thelike); (d) disintegrating agents (e.g., agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates,sodium carbonate and the like); (e) solution retarders (e.g., paraffinand the like); (f) absorption accelerators (e.g., quaternary ammoniumcompounds and the like); (g) wetting agents (e.g., cetyl alcohol,glycerol monostearate and the like); (h) adsorbents (e.g., kaolin,bentonite and the like); and/or (i) lubricants (e.g., talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate and the like). In the case of capsules and tablets, the dosageforms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in softor hard filled gelatin capsules using such excipients as lactose or milksugar, as well as high molecular weight polyethylene glycols, and thelike.

Solid dosage forms such as tablets, dragees, capsules, and granules canbe prepared with coatings and shells, such as enteric coatings andothers well known in the art. They may also contain opacifying agents,and can also be of such composition that they release the compound ofthe present invention and/or the additional pharmaceutical agent in adelayed manner. Examples of embedding compositions that can be used arepolymeric substances and waxes. The drug can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the compound of the present invention or the combination,the liquid dosage form may contain inert diluents commonly used in theart, such as water or other solvents, solubilizing agents andemulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seedoil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of thesesubstances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the compound of the present invention or thecombination, may further comprise suspending agents, e.g., ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, or mixtures of these substances, and thelike.

Compositions for rectal or vaginal administration preferably comprisesuppositories, which can be prepared by mixing a compound of the presentinvention or a combination with suitable non-irritating excipients orcarriers, such as cocoa butter, polyethylene glycol or a suppository waxwhich are solid at ordinary room temperature but liquid at bodytemperature and therefore melt in the rectum or vaginal cavity therebyreleasing the active component(s).

Dosage forms for topical administration of the compounds of the presentinvention and combinations of the compounds of the present inventionwith anti-obesity agents may comprise ointments, powders, sprays andinhalants. The drugs are admixed under sterile condition with apharmaceutically acceptable carrier, and any preservatives, buffers, orpropellants that may be required. Ophthalmic formulations, eyeointments, powders, and solutions are also intended to be includedwithin the scope of the present invention.

The following paragraphs describe exemplary formulations, dosages, etc.useful for non-human animals. The administration of the compounds of thepresent invention and combinations of the compounds of the presentinvention with anti-obesity agents can be effected orally or non-orally(e.g., by injection).

An amount of a compound of the present invention or combination of acompound of the present invention with an anti-obesity agent isadministered such that an effective dose is received. Generally, a dailydose that is administered orally to an animal is between about 0.01 andabout 1,000 mg/kg of body weight, preferably between about 0.01 andabout 300 mg/kg of body weight.

Conveniently, a compound of the present invention (or combination) canbe carried in the drinking water so that a therapeutic dosage of thecompound is ingested with the daily water supply. The compound can bedirectly metered into drinking water, preferably in the form of aliquid, water-soluble concentrate (such as an aqueous solution of awater-soluble salt).

Conveniently, a compound of the present invention (or combination) canalso be added directly to the feed, as such, or in the form of an animalfeed supplement, also referred to as a premix or concentrate. A premixor concentrate of the compound in a carrier is more commonly employedfor the inclusion of the agent in the feed. Suitable carriers are liquidor solid, as desired, such as water, various meals such as alfalfa meal,soybean meal, cottonseed oil meal, linseed oil meal, corncob meal andcorn meal, molasses, urea, bone meal, and mineral mixes such as arecommonly employed in poultry feeds. A particularly effective carrier isthe respective animal feed itself; that is, a small portion of suchfeed. The carrier facilitates uniform distribution of the compound inthe finished feed with which the premix is blended. Preferably, thecompound is thoroughly blended into the premix and, subsequently, thefeed. In this respect, the compound may be dispersed or dissolved in asuitable oily vehicle such as soybean oil, corn oil, cottonseed oil, andthe like, or in a volatile organic solvent and then blended with thecarrier. It will be appreciated that the proportions of compound in theconcentrate are capable of wide variation since the amount of thecompound in the finished feed may be adjusted by blending theappropriate proportion of premix with the feed to obtain a desired levelof compound.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the compound across thetop of the dressed feed.

Drinking water and feed effective for increasing lean meat depositionand for improving lean meat to fat ratio are generally prepared bymixing a compound of the present invention with a sufficient amount ofanimal feed to provide from about 10⁻³ to about 500 ppm of the compoundin the feed or water.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from about 1 to about 400 grams of a compound of the presentinvention (or combination) per ton of feed, the optimum amount for theseanimals usually being about 50 to about 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 toabout 400 grams and preferably about 10 to about 400 grams of a compoundof the present invention (or combination) per ton of feed.

For parenteral administration in animals, the compounds of the presentinvention (or combination) may be prepared in the form of a paste or apellet and administered as an implant, usually under the skin of thehead or ear of the animal in which increase in lean meat deposition andimprovement in lean meat to fat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of a compound of the present invention (or combination) toprovide the animal with about 0.01 to about 20 mg/kg/day of body weightof the drug. The preferred dosage for poultry, swine, cattle, sheep,goats and domestic pets is in the range of from about 0.05 to about 10mg/kg/day of body weight of drug.

Paste formulations can be prepared by dispersing the drug in apharmaceutically acceptable oil such as peanut oil, sesame oil, corn oilor the like.

Pellets containing an effective amount of a compound of the presentinvention, pharmaceutical composition, or combination can be prepared byadmixing a compound of the present invention or combination with adiluent such as carbowax, carnuba wax, and the like, and a lubricant,such as magnesium or calcium stearate, can be added to improve thepelleting process.

It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, implants may also be madeperiodically during the animal treatment period in order to maintain theproper drug level in the animal's body.

The present invention has several advantageous veterinary features. Forthe pet owner or veterinarian who wishes to increase leanness and/ortrim unwanted fat from pet animals, the instant invention provides themeans by which this may be accomplished. For poultry and swine breeders,utilization of the method of the present invention yields leaner animalsthat command higher sale prices from the meat industry.

Embodiments of the present invention are illustrated by the followingExamples. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of these Examples, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

EXAMPLES

Unless specified otherwise, starting materials are generally availablefrom commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wis.),Lancaster Synthesis, Inc. (Windham, N.H.), Acros Organics (Fairlawn,N.J.), Maybridge Chemical Company, Ltd. (Cornwall, England), TygerScientific (Princeton, N.J.), and AstraZeneca Pharmaceuticals (London,England).

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 (available from VarianInc., Palo Alto, Calif.) at room temperature at 400 MHz for proton.Chemical shifts are expressed in parts per million (δ) relative toresidual solvent as an internal reference. The peak shapes are denotedas follows: s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; bs, broad singlet; 2s, two singlets. Atmospheric pressurechemical ionization mass spectra (APCI) were obtained on a FisonS™Platform II Spectrometer (carrier gas: acetonitrile: available fromMicromass Ltd, Manchester, UK). Chemical ionization mass spectra (CI)were obtained on a Hewlett-Packard™ 5989 instrument (ammonia ionization,PBMS: available from Hewlett-Packard Company, Palo Alto, Calif.).Electrospray ionization mass spectra (ES) were obtained on a Waters™ ZMDinstrument (carrier gas: acetonitrile: available from Waters Corp.,Milford, Mass.). Where the intensity of chlorine or bromine-containingions are described, the expected intensity ratio was observed(approximately 3:1 for ³⁵CI/³⁷CI-containing ions and 1:1 for⁷⁹Br/⁸¹Br-containing ions) and the intensity of only the lower mass ionis given. In some cases only representative ¹H NMR peaks are given. MSpeaks are reported for all examples. Optical rotations were determinedon a PerkinElmer™ 241 polarimeter (available from PerkinElmer Inc.,Wellesley, Mass.) using the sodium D line (λ=589 nm) at the indicatedtemperature and are reported as follows [α]_(D) ^(temp), concentration(c=g/100 mL), and solvent.

Column chromatography was performed with either Baker™ silica gel (40μm; J. T. Baker, Phillipsburg, N.J.) or Silica Gel 50 (EM Sciences™,Gibbstown, N.J.) in glass columns or in Flash 40 Biotage™ columns (ISC,Inc., Shelton, Conn.) under low nitrogen pressure.

Example 1 Preparation of Intermediate4-(2-Chloro-pyrimidin-4-yl)-niperazine-1-carboxylic acid tert-butylester (I-1a)

To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in 100 mL ofethanol was added powdered sodium carbonate (2.1 g, 20.1 mmol) andpiperazine-1-carboxylic acid tert-butyl ester (3.75 g, 20.1 mmol). Thereaction was heated to reflux for 5 hours, then cooled to roomtemperature and concentrated in vacuo. The residue was taken up in 400mL of ethyl acetate and extracted with water (100 mL) and brine (100mL). The organic phase was then dried over sodium sulfate, filtered, andconcentrated in vacuo to a clear oil. Flash column chromatography(silica gel, gradient elution from 10% ethyl acetate-hexanes to 50%ethyl acetate-hexanes) yielded 4.63 g of the title compound (I-1a).

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, 1H), 6.39 (d, 1H), 3.65-3.50 (m, 8H),1.46 (s, 9H). MS (ES+) Calc: 298, Found: 299.1 (M+1).

Preparation of Intermediate4-[2-(3,5-Difluoro-benzyloxy)-nyrimidin-4-yl]-pinerazine-1-carboxylicacid tert-butyl ester (I-1b)

3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred undernitrogen for 15 minutes at ambient temperature, then the reaction wastreated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acidtert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. Theresultant mixture was refluxed under nitrogen for 4 hours. After coolingto room temperature, the reaction was poured into water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic extractswere washed with brine (20 mL), then dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2mg of the title product (1-1 b).

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, 1H); 6.96 (d, 2H); 6.72 (t, 1H); 6.20(d, 1H); 5.33 (s, 2H); 3.63 (bs, 4H); 3.50 (m, 4H); 1.47 (s, 9H). MS(ES⁺) Calc: 406.4, Found: 407.3 (M+1).

Preparation of 2-(3,5-Difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine(1-A)

To a solution of4-[2-(3,5-difluoro-benzyloxy)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (I-1b) (605.2 mg, 1.49 mmol) in 5 mL ofdichloromethane was added trifluoroacetic acid (1.72 mL, 22.33 mmol) andthe mixture was stirred for 3 h at ambient temperature. The reaction wasconcentrated in vacuo, and the residue dissolved in 1 M HCl_((aq)) (70mL). This was extracted with ethyl acetate (40 mL), separated, and theaqueous layer was adjusted to a pH of 12 using 5 M KOH_((aq)). Thisaqueous mixture was extracted with dichloromethane (2×100 mL) and thecombined organic extracts were dried over sodium sulfate andconcentrated to give 414.3 mg of a clear colorless oil that wasdetermined to be title compound (1-A).

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, 1H); 7.02 (dd, 2H); 6.84 (dt, 1H);6.37 (d, 1H); 5.34 (s, 2H); 3.62 (bs, 4H); 2.81 (m, 4H). MS (APCI⁺)Calc: 306.3, Found: 307.3 (M+1).

Preparation of 2-(3,5-Difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride (1-B)

2-(3,5-Difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine (1-A) (27.5 mg,0.09 mmol) was dissolved in 1 mL of dichloromethane and treated with 1 Mhydrogen chloride in ether (89.8 μL, 0.09 mmol) and shaken for oneminute. The reaction was then concentrated under a stream of nitrogen togive 30.8 mg of a yellow solid as the title compound (1-B).

¹H NMR (400 MHz, CD₃OD) δ 8.09 (d, 1H); 7.05 (dd, 2H); 6.88 (dt, 1H);6.54 (d, 1H); 5.39 (s, 2H); 3.93 (m, 4H); 3.28 (m, 4H). MS (APCI⁺) Calc:306.3, Found: 307.1 (M+1).

Preparation of 2-(3,5-Difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,fumarate (1-C)

2-(3,5-Difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine (1-A) (414.3 mg,1.35 mmol) was dissolved in 10 mL of 10:1 methanol:isopropyl ether andtreated with a solution of 0.5 M fumaric acid in methanol (2.70 mL, 1.35mmol) and stirred for 1 h. The resulting slurry was diluted with 35 mLof isopropyl ether and stirred for 10 min. Filtration followed by airdrying provided 549.4 mg of the title compound (1-C).

¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, 1H); 7.03 (dd, 2H); 6.86 (dt, 1H);6.67 (s, 2H); 6.49 (d, 1H); 5.37 (s, 2H); 3.87 (m, 4H); 3.19 (m, 4H). MS(APCI⁺) Calc: 306.3, Found: 307.1 (M+1).

Using the appropriate starting materials, the compounds listed in Table1 were prepared in an analogous manner to the sequence of reactionsdescribed above for the preparation of compound (1-A) and thecorresponding hydrochloride and fumarate salts (1-B) and (1-C),respectively. TABLE 1 MS EX. Found No. Compound Name Calc. (M + 1) 1-D4-Methyl-2-(3-phenoxy-benzyloxy)-6- 376.4 377.1piperazin-1-yl-pyrimidine 1-E 2-[1-(3-Fluoro-phenyl)-ethoxy]-4-methyl-6-316.4 317.2 piperazin-1-yl-pyrimidine 1-F4-Methyl-6-piperazin-1-yl-2-(3- 368.4 369.1trifluoromethoxy-benzyloxy)-pyrimidine 1-G2-(4-Chloro-benzyloxy)-4-methyl-6-piperazin- 318.0 319.1 1-yl-pyrimidine1-H 2-[1-(2-Chloro-phenyl)-ethoxy]-4-methyl-6- 332.0 333.1piperazin-1-yl-pyrimidine 1-I2-(3-Chloro-benzyloxy)-4-methyl-6-piperazin- 318.0 319.1 1-yl-pyrimidine1-J 2-[1-(3-Chloro-phenyl)-ethoxy]-4-methyl-6- 332.0 333.1piperazin-1-yl-pyrimidine 1-K 2-(3-Methoxy-benzyloxy)-4-piperazin-1-yl-300.4 301.2 pyrimidine 1-L 2-[1-(3-Fluoro-phenyl)-ethoxy]-4-piperazin-1-302.3 303.2 yl-pyrimidine 1-M 4-Piperazin-1-yl-2-(3-trifluoromethoxy-354.3 355.1 benzyloxy)-pyrimidine 1-N2-(3-Chloro-benzyloxy)-4-piperazin-1-yl- 304.0 305.1 pyrimidine 1-O2-[1-(3-Chloro-phenyl)-ethoxy]-4-piperazin-1- 318.0 319.1 yl-pyrimidine1-P 2-Benzyloxy-4-methyl-6-piperazin-1-yl- 320.2 321.1 pyrimidine,hydrochloride 1-Q 2-(4-Chloro-benzyloxy)-4-piperazin-1-yl- 304.0 305.1pyrimidine 1-R 2-[1-(2-Chloro-phenyl)-ethoxy]-4-piperazin-1- 318.0 319.1yl-pyrimidine 1-S 2-(3,4-Dichloro-benzyloxy)-4-piperazin-1-yl- 338.0339.0 pyrimidine 1-T 2-(4-Fluoro-benzyloxy)-4-piperazin-1-yl- 288.1289.1 pyrimidine 1-U 2-(3,4-Difluoro-benzyloxy)-4-piperazin-1-yl- 306.1307.1 pyrimidine 1-V 2-(2-Chloro-benzyloxy)-4-piperazin-1-yl- 304.1305.1 pyrimidine, hydrochloride 1-W2-(2-Fluoro-benzyloxy)-4-piperazin-1-yl- 288.1 289.1 pyrimidine,hydrochloride 1-X 2-(3-Fluoro-benzyloxy)-4-piperazin-1-yl- 288.1 289.1pyrimidine, hydrochloride 1-Y2-(2,3-Difluoro-benzyloxy)-4-piperazin-1-yl- 306.1 307.1 pyrimidine,hydrochloride 1-Z 2-(2,5-Difluoro-benzyloxy)-4-piperazin-1-yl- 306.1307.1 pyrimidine, hydrochloride 1-AA2-(2,6-Difluoro-benzyloxy)-4-piperazin-1-yl- 306.1 307.1 pyrimidine,hydrochloride 1-BB 2-(2-Chloro-6-fluoro-benzyloxy)-4-piperazin-1- 322.1323.1 yl-pyrimidine, hydrochloride 1-CC2-(3-Chloro-benzyloxy)-4-piperazin-1-yl- 304.1 305.1 pyrimidine,hydrochloride 1-DD 2-(2-Chloro-pyridin-3-ylmethoxy)-4-piperazin- 305.1306.0 1-yl-pyrimidine, hydrochloride 1-EE2-(2,5-Dichloro-benzyloxy)-4-piperazin-1-yl- 338.1 338.9 pyrimidine,hydrochloride 1-FF 2-(2,6-Dichloro-benzyloxy)-4-piperazin-1-yl- 338.1338.9 pyrimidine, hydrochloride 1-GG2-(2,3-Dichloro-benzyloxy)-4-piperazin-1-yl- 338.1 339.0 pyrimidine,hydrochloride 1-HH 2-(3,5-Dichloro-benzyloxy)-4-piperazin-1-yl- 338.1339.0 pyrimidine, hydrochloride 1-II4-Piperazin-1-yl-2-(2-trifluoromethoxy- 354.1 355.1benzyloxy)-pyrimidine, hydrochloride 1-JJ4-Piperazin-1-yl-2-(2-trifluoromethyl- 338.1 339.1benzyloxy)-pyrimidine, hydrochloride 1-KK2-(3-Chloro-benzyloxy)-4-[(2S)-methyl- 318.1 319.1piperazin-1-yl]-pyrimidine, hydrochloride 1-LL2-(3-Chloro-benzyloxy)-4-[(2R)-methyl- 318.1 319.1piperazin-1-yl]-pyrimidine, hydrochloride 1-MM2-(3-Chloro-benzyloxy)-4-[(3R)-methyl- 318.1 319.1piperazin-1-yl]pyrimidine 1-NN2-(3-Chloro-benzyloxy)-4-[(3R,5S)-dimethyl- 332.1 333.1piperazin-1-yl]-pyrimidine 1-OO4-Piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)- 324.1 325.1 pyrimidine1-PP 2-(5-Fluoro-2-trifluoromethyl-benzyloxy)-4- 356.1 357.1piperazin-1-yl-pyrimidine 1-QQ 2-(3,5-Bis-trifluoromethyl-benzyloxy)-4-406.1 407.1 piperazin-1-yl-pyrimidine 1-RR2-(2,5-Dichloro-benzyloxy)-4-[(2R)-methyl- 352.1 353.2piperazin-1-yl]-pyrimidine 1-SS2-(3,5-Dichloro-benzyloxy)-4-[(2R)-methyl- 352.1 353.2piperazin-1-yl]-pyrimidine 1-TT2-(2,5-Difluoro-benzyloxy)-4-[(2R)-methyl- 320.1 321.3piperazin-1-yl]-pyrimidine 1-UU2-(3,5-Difluoro-benzyloxy)-4-[(2R)-methyl- 320.1 321.3piperazin-1-yl]-pyrimidine 1-VV2-(2,5-Dichloro-benzyloxy)-4-[(2S)-methyl- 352.1 353.2piperazin-1-yl]-pyrimidine 1-WW2-(2,5-Difluoro-benzyloxy)-4-[(2S)-methyl- 320.1 321.2piperazin-1-yl]-pyrimidine 1XX2-(3,5-Difluoro-benzyloxy)-4-[(2S)-methyl- 320.1 321.3piperazin-1-yl]-pyrimidine 1-YY4-Piperazin-1-yl-2-(3,4,5-trifluoro-benzyloxy)- 324.1 325.3 pyrimidine1-ZZ 2-(3-Fluoro-5-trifluoromethyl-benzyloxy)-4- 356.1 357.3piperazin-1-yl-pyrimidine 1-AB2-[1-(3,5-Difluoro-phenyl)-ethoxy]-4-piperazin- 320.1 321.31-yl-pyrimidine 1-AC 2-(3,5-Dichloro-benzyloxy)-4-[(2S)-methyl- 352.1353.2 piperazin-1-yl]-pyrimidine 1-AD2-(3,5-Dimethyl-benzyloxy)-4-piperazin-1-yl- 298.1 299.3 pyrimidine 1-AE2-(2,5-Dimethyl-benzyloxy)-4-piperazin-1-yl- 298.1 299.3 pyrimidine 1-AF2-[(1R)-Phenyl-ethoxy]-4-piperazin-1-yl- 284.4 285.3 pyrimidine 1-AG2-[(1S)-Phenyl-ethoxy]-4-piperazin-1-yl- 284.4 285.3 pyrimidine 1-AH2-(3-Chloro-benzyloxy)-4-[(3S)-methyl- 318.1 319.5piperazin-1-yl]-pyrimidine 1-AI 2-(3-Fluoro-benzyloxy)-4-[(3S)-methyl-302.3 303.6 piperazin-1-yl]-pyrimidine 1-AJ2-Benzyloxy-4-piperazin-1-yl-pyrimidine, 306.3 307.3 hydrochloride 1-AK2-Benzyloxy-5-methyl-4-piperazin-1-yl- 320.0 321.1 pyrimidine,hydrochloride 1-AL 2-(3-Methoxy-benzyloxy)-4-methyl-6- 314.4 315.4piperazin-1-yl-pyrimidine

Example 2 Preparation of Intermediate4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butylester (I-2a)

To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mLof toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butylester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight,then cooled to room temperature and concentrated in vacuo. The residuewas taken up in 20 mL of water and extracted with ethyl acetate (2×40mL). The combined organic layers were washed with brine (25 mL), thendried over sodium sulfate, filtered, and concentrated in vacuo to anoff-white solid. Flash column chromatography (silica gel, gradientelution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes)yielded 1.14 g of the title compound (I-2a).

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, 1H); 6.52 (d, 1H); 3.80 (m, 4H); 3.48(m, 4H); 1.47 (s, 9H). MS (APCI⁺) Calc: 298, Found: 299.1 (M+1).

Preparation of Intermediate4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester (I-2b)

1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg,60% dispersion in mineral oil, 0.20 mmol). This was stirred undernitrogen for 1 hour at ambient temperature, then the reaction wastreated with 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester (1-2a) (50 mg, 0.17 mmol) in one portion. The resultantmixture was refluxed under nitrogen for 4 hours. After cooling to roomtemperature, the reaction was poured into water (20 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic extracts were washedwith brine (20 mL), then dried over sodium sulfate, filtered, andconcentrated. The residue was purified by preparative TLC (7:13 ethylacetate:hexanes) to afford 64.3 mg of the title product (I-2b).

¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, 1H); 7.38-7.13 (m, 4H); 6.35 (q, 1H);6.02 (d, 1H); 3.62 (m, 4H); 3.30 (m, 4H); 1.57 (d, 3H); 1.45 (s, 9H). MS(APCI⁺) Calc: 418, Found: 419.1 (M+1).

Preparation of4-[1-(2-Chloro-phenyl)-ethoxy]-2-piperazin-1-yl-pyrimidine (2-A)

To a solution of4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester (1-2b) (64.3 mg, 0.15 mmol) in 2.0 mL ofdichloromethane was added trifluoroacetic acid (177.4 μL, 2.30 mmol) andthe mixture was stirred for 1.5 h at ambient temperature. The reactionwas concentrated, and the residue dissolved in 1 M HCl_((aq)) (10 mL).This was extracted with ethyl acetate (10 mL), separated, and theaqueous layer was adjusted to a pH of 12 using 5 M KOH_((aq)). Thisaqueous mixture was extracted with ethyl acetate (2×15 mL) and thecombined organic extracts were dried over sodium sulfate andconcentrated to give 58.2 mg of the title product (2-A).

¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H); 7.38 (dd, 1H); 7.28 (d, 1H);7.18-7.11 (m, 2H); 6.36 (q, 1H); 6.00 (d, 1H); 3.68 (bs, 4H); 2.82 (bs,4H); 1.56 (d, 3H). MS (APCI⁺) Calc: 318, Found: 319.1 (M+1).

Preparation of4-[1-(2-Chloro-phenyl)-ethoxy]-2-piperazin-1-yl-pyrimidine,trifluoroacetate (2-B)

To a solution of4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylicacid tert-butyl ester (1-2b) (64.3 mg, 0.15 mmol) in 2.0 mL ofdichloromethane was added trifluoroacetic acid (177.4 μL, 2.30 mmol) andthe mixture was stirred for 1.5 h at ambient temperature. The reactionwas concentrated, and the residue solvent exchanged 6×4 mL of hexanes.The residue was found to be 62.1 mg of the title compound (2-B).

¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H); 7.38 (dd, 1H); 7.28 (d, 1H);7.18-7.11 (m, 2H); 6.36 (q, 1H); 6.00 (d, 1H); 3.68 (bs, 4H); 2.82 (bs,4H); 1.56 (d, 3H). MS (APCI⁺) Calc: 318, Found: 319.1 (M+1).

Using the appropriate starting materials, the compounds listed in Table2 were prepared in an analogous manner to the sequence of reactionsdescribed above for the preparation of compound (2-A) and thecorresponding trifluoroacetate salt (2-B). The hydrochloride salt wasformed in a manner analogous to the procedure described for theformation of (1-B) in Example 1. TABLE 2 MS Ex. Found No. Compound NameCalc. (M + 1) 2-C 4-[1-(3-Chloro-phenyl)-ethoxy]-2-piperazin- 318.0319.2 1-yl-pyrimidine 2-D 4-[1-(4-Chloro-phenyl)-ethoxy]-2-piperazin-318.0 319.2 1-yl-pyrimidine 2-E 4-(4-Fluoro-benzyloxy)-2-piperazin-1-yl-288.3 289.2 pyrimidine 2-F 4-(3,4-Dichloro-benzyloxy)-2-piperazin-1-yl-338.0 339.0 pyrimidine 2-G 4-(3,4-Difluoro-benzyloxy)-2-piperazin-1-yl-306.3 307.1 pyrimidine 2-H 4-(3,4-Dimethyl-benzyloxy)-2-piperazin-1-298.2 299.2 yl-pyrimidine, hydrochloride 2-I4-(2,3-Difluoro-benzyloxy)-2-piperazin-1-yl- 306.1 307.1 pyrimidine,trifluoroacetate 2-J 4-[1-(3-Chloro-phenyl)-ethoxy]-6-methyl-2- 332.1333.3 piperazin-1-yl-pyrimidine, trifluoroacetate 2-K4-(2-Ethoxy-benzyloxy)-6-methyl-2- 328.4 329.3piperazin-1-yl-pyrimidine, trifluoroacetate 2-L4-Benzyloxy-2-piperazin-1-yl-pyrimidine, 343.3 344.3 hydrochloride

Example 3 Preparation of Intermediate4-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-piperazine-1-carboxylic acidtert-butyl ester (I-3a)

A mixture of 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acidtert-butyl ester (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) washeated at reflux for 7 days. The reaction mixture was cooled to roomtemperature, poured into H₂O (15 mL) and extracted with EtOAc (2×20 mL).The combined organic extracts were washed with H₂O (3×15 mL), brine,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative TLC (10% MeOH in CH₂Cl₂) to give a yellow solid. The yellowsolid was triturated with MeOH (1 mL) and the solid was collected byfiltration to give intermediate (I-3a) as a white solid (48.5 mg).

¹H NMR (400 MHz, CD₃OD) δ 7.74 (bs, 1H); 7.35-7.17 (m, 4H); 6.01 (bs,1H); 4.45 (s, 2H); 3.54 (bs, 4H); 3.37 (bs, 4H); 1.44 (s, 9H). MS (ES⁺)Calc: 403.2, Found: 404.1 (M+1).

Preparation of(3-Chloro-benzyl)-(4-piperazin-1-yl-Pyrimidin-2-yl)-amine, hydrochloride(3-A)

To a solution of4-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-piperazine-1-carboxylic acidtert-butyl ester (I-3a) (48.5 mg, 0.12 mmol) in CH₂Cl₂ (1 mL) was addedtrifluoroacetic acid (139 μL, 1.8 mmol). After stirring at roomtemperature for 3 h, the mixture was poured into 1 N NaOH (10 mL) andextracted with CH₂Cl₂ (1×35 mL). The organic layer was washed withbrine, dried and concentrated to afford the title compound as a freeamine. The free amine in CH₂Cl₂ (1 mL) was added to 1 M HCl in ether(0.10 mL, 0.10 mmol). After stirring for 10 min at room temperature, thesolution was concentrated in vacuo to yield the hydrochloride salt (3-A)(32.4 mg) as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, 1H); 7.38 (s, 1H); 7.35-7.26 (m, 3H);6.51 (d, 1H); 4.60 (s, 2H); 4.04 (bs, 4H); 3.29 (bs, 4H). MS (APCI⁺)Calc: 303.2, Found: 304.1 (M+1).

Preparation of(3-Chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine, fumarate(3-B)

To a solution of intermediate (I-3a) (274.2 mg, 0.90 mmol) in 10 mL of10:1 methanol:isopropyl ether was added a solution of 0.5 M fumaric acidin methanol (1.80 mL, 0.90 mmol) and stirred for 1 h. The resultingslurry was diluted with 35 mL of isopropyl ether and stirred for 10 min.Filtration followed by air drying provided 356.8 mg of the titlecompound (3-B).

¹H NMR (400 MHz, CD₃OD) δ 7.81 (d, 1H); 7.32-7.18 (m, 4H); 6.67 (s, 2H);6.16 (d, 1H); 4.50 (s, 2H); 3.80 (bs, 4H); 3.11 (bs, 4H). MS (APCI⁺)Calc: 303.2, Found: 304.3 (M+1).

Using the appropriate starting materials, the following compounds wereprepared in an analogous manner to the sequence of reactions describedfor compound (3-A) above.

(3-Fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine, hydrochloride(3-C)

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, 1H); 7.30-7.26 (m, 1H); 7.12 (d, 1H);7.05-7.02 (dd, 1H); 6.92-6.91 (td, 1H); 6.16 (d, 1H); 4.52 (s, 2H);3.81-3.78 (m, 4H); 3.12-3.11 (m, 4H). MS (APCI⁺) Calc: 287.2, Found:288.1 (M+1).

Benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine, hydrochloride (3-D)

MS (APCI⁺) Calc: 305.3, Found: 306.2 (M+1).

Example 4 Preparation of Intermediate4-[4-(3-Chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic acidtert-butyl ester (I-4a)

A mixture of 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL,5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL)was heated at reflux for 24 h. The reaction mixture was cooled to roomtemperature, poured into H₂O (15 mL) and extracted with EtOAc (2×18 mL).The combined organic extracts were washed with H₂O (2×10 mL), brine,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bychromatography using 40% EtOAc in hexane as an eluting solvent to affordthe title compound I-4a (93 mg) as a colorless oil.

¹H NMR (400 MHz, CD₃OD) δ 7.69 (d, 1H); 7.32 (s, 1H); 7.28-7.19 (m, 3H);5.88 (d, 1H); 4.49 (s, 2H); 3.64-3.61 (m, 4H); 3.37-3.29 (m, 4H); 1.45(s, 9H). MS (ES⁺) Calc: 403.2, Found: 404.0 (M+1).

Preparation of(3-Chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, hydrochloride(4-A)

The title compound (4-A) was prepared from4-[4-(3-chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic acidtert-butyl ester (I-4a) and TFA according to a procedure analogous tothat described in Example 3.

¹H NMR (400 MHz, CD₃OD) δ 7.74 (d, 1H); 7.35-7.25 (m, 4H); 6.15 (d, 1H);4.60 (s, 2H); 3.97-3.94 (m, 4H); 3.27-3.23 (m, 4H). MS (APCI⁺) Calc:303.2, Found: 304.1 (M+1).

Using the appropriate starting materials, compound (4-B) was prepared inan analogous manner to the sequence of reactions described for compound(4-A) above and the corresponding fumarate salt (4-C) was prepared usinga procedure analogous to the process for preparing the fumarate saltdescribed in Example 3 (compound (3-B)).

(3-Fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, hydrochloride(4-B)

¹H NMR (400 MHz, CD₃OD) δ 7.76 (d, 1H); 7.32-7.28 (m, 1H); 7.11 (d, 1H),7.05-7.01 (dd, 1H), 6.93 (td, 1H); 5.94 (d, 1H); 4.53 (s, 2H); 3.90-3.87(m, 4H); 3.13-3.11 (m, 4H). MS (APCI⁺) Calc: 287.2, Found: 288.1 (M+1).

(3-Fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate(4-C)

¹H NMR (400 MHz, CD₃OD) δ 7.75 (d, 1H); 7.30 (dd, 1H); 7.11 (d, 1H),7.02 (d, 1H), 6.93 (td, 1H); 6.69 (s, 3H) 5.94 (d, 1H); 4.53 (s, 2H);3.87 (m, 4H); 3.13-3.11 (m, 4H). MS (APCI⁺) Calc: 287.2, Found: 288.1(M+1).

Benzyl-(2-piperazin-1-yl-Pyrimidin-4-yl)-amine, hydrochloride (4-D)

MS (APCI⁺) Calc: 305.3, Found: 306.2 (M+1).

Example 5 Preparation of Intermediate (6-Chloro-pyridin-2-yl)-methanol(I-5a)

A dry flask was charged with 25 mL of anhydrous tetrahydrofuran and6-chloropyridine-2-carboxylic acid (2.00 g, 12.69 mmol) and then cooledto 10° C. This was treated dropwise with tetrahydrofuran-borane (1.0 Msolution in THF, 38.1 mL) over 10 minutes under nitrogen. This wasstirred with cooling for 15 minutes, then at ambient temperature for 4h. The reaction was then cooled to 0° C., and 10 mL of water were addedslowly. The resultant mixture was poured into 50 mL of 1 M aqueoussodium hydroxide and extracted 2×75 mL of ethyl acetate. The organicextracts were combined and washed with brine, then dried over sodiumsulfate and filtered. Concentration in vacuo yielded 589.1 mg of a whitesolid as the title compound (I-5a).

¹H NMR (400 MHz, CDCL₃) δ 7.67 (t, 1H); 7.25 (m, 2H); 4.74 (s, 2H). MS(ES⁺) Calc: 143, Found: 144.3 (M+1).

Preparation of Intermediate4-[2-(6-Chloro-pyridin-2-ylmethoxy)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (I-5b)

The title compound (I-5b) was prepared from(6-chloro-pyridin-2-yl)-methanol (I-5a) and4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butylester (I-1a) according to a procedure analogous to that described inExample 1.

¹H NMR (400 MHz, CDCL₃) δ 8.03 (d, 1H); 7.63 (t, 1H); 7.43 (d, 1H); 7.21(d, 1H); 6.16 (d, 1H); 5.42 (s, 2H); 3.59 (m, 4H); 3.45 (m, 4H); 1.46(s, 9H). MS (ES+) Calc: 405, Found: 406.1 (M+1).

Preparation of2-(6-Chloro-Pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine,hydrochloride (5-A)

The title compound (5-A) was prepared from4-[2-(6-chloro-pyridin-2-ylmethoxy)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (I-5b) and TFA according to a procedure analogousto that described in Example 3.

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, 1H); 7.80 (t, 1H); 7.46 (d, 1H); 7.36(d, 1H); 6.53 (d, 1H); 5.41 (s, 2H); 3.91 (m, 4H); 3.27 (m, 4H). MS(ES⁺) Calc: 305, Found: 306.0 (M+1).

Using the appropriate starting materials, the compounds listed in Table4 were prepared in an analogous manner to the sequence of reactionsdescribed above for the preparation of compound (5-A). TABLE 4 MS Ex.Found No. Compound Name Calc. (M + 1) 5-B4-Piperazin-1-yl-2-(pyridin-2-ylmethoxy)- 271.1 272.0 pyrimidine,hydrochloride 5-C 2-(6-Methyl-pyridin-2-ylmethoxy)-4- 285.1 286.0piperazin-1-yl-pyrimidine, hydrochloride

Example 6

Example 6 illustrates the synthesis of NEPiCompound—(S)-2-[(1-{[3-(4-chlorophenyl)propyl]carbamoyl}cyclopentyl)methyl]-4-methoxy-butanoicacid referred to herein below for use in combination with the compoundsof the present invention for treating female sexual dysfunction.

Preparation of Intermediate1-[2-(tert-Butoxycarbonyl)-4-methoxybutyl]-cyclopentanecarboxylic acid(I-6a)

A solution of tert-butyl 3-(1-carboxycyclopentyl)propanoate (12 g, 49.5mmol) (see EP274234B1, Example 35) in dry tetrahydrofuran (100 ml) wasadded to a stirred solution of lithium diisopropylamide (130 ml) in amixture of hexane (52 ml) and tetrahydrofuran (200 ml) at −78° C. undernitrogen. After 1 hour a solution of 2-bromoethyl methyl ether intetrahydrofuran (100 ml) was added maintaining the temperature at −78°C. The reaction mixture was allowed to warm up to room temperatureovernight. The mixture was quenched with water (100 ml) and acidified topH 1 with 2M hydrochloric acid, and extracted with ethyl acetate (2×150ml). The combined organic extracts were dried over magnesium sulfate andconcentrated in vacuo to give the crude acid which was chromatographedon silica. Elution with increasing proportions of methanol indichloromethane (neat dichloromethane to 1:50) gave an oil (7.7 g, 25.6mmol, 52%); Rf 0.3 methanol, dichloromethane 1:20;

¹H NMR (CDCl₃ 400 MHz) δ: 1.4 (s, 9H), 1.4-1.7 (m, 7H), 1.75-1.95 (m,2H), 2.0-2.15 (m, 3H), 2.3-2.4 (m, 1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H);LRMS: m/z 299 (M−H⁺).

Preparation of Intermediate1-[(2S)-2-(tert-Butoxycarbonyl)-4-methoxybutyl]-cyclopentanecarboxylicacid (I-6b)

Intermediate I-6a and (+)-pseudoephedrine were recrystallised nine timesfrom hexane to give a white crystaline solid. The salt was dissolved inethyl acetate washed with 0.5M hydrochloric acid dried over magnesiumsulphate and concentrated in vacuo the (S)-acid was obtained in 31%yield as a pale yellow oil in >90% ee (enantiomeric excess) by NMRanalysis of the δ 3.3 peak of the (+)-pseudoephedrine salt;

¹H NMR (CDCl₃ 400 MHz) δ: 1.4 (s, 9H), 1.4-1.7 (m, 7H), 1.75-1.9 (m,2H), 2.0-2.15 (m, 3H), 2.35-2.45 (m, 1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H);[α]_(D)−5.2 (EtOH, c 1.2).

Preparation of Intermediate tert-butyl(2S)-2-{[1-({[3-(4-chlorophenyl-propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoate (I-6c)

To a solution of 1,1′-carbonyl diimidazole (73.9 g, 0.45 mol) inazeotropically dried isopropyl acetate (339 ml) was added the isopropylacetate solution of the Intermediate I-6b with stirring at 60° C. underan atmosphere of N₂ over a period of 1.5 hours. The transfer lines werethen washed with dry isopropyl acetate (50 ml). The resultant solutionwas then stirred at 60° C. for a further 4.5 hours and then the reactionmixture was allowed to cool to room temperature and stirred for 15hours. To the resultant solution was then added triethylamine (46.1 g,0.46 mol), followed by 3-(4-chlorophenyl)-propylamine hydrochloride (J.Med. Chem., 1996, 39, 4942-51)(94.3 g, 0.46 mol). The resultant mixturewas then heated to 60° C. for 7 hours before cooling to roomtemperature. Deionised water (100 ml) was then added to the reactionmixture with stirring, followed by aqueous hydrochloric acid (190 ml ofa 5 M solution) until the pH of the aqueous layer was between pH 2 and3. The aqueous layer was then separated, and the organic layer waswashed with aqueous potassium carbonate (50 ml of a 0.5 M solution). Theaqueous phase was separated and organic phase was washed with saturatedbrine solution (100 ml). The aqueous layer was then separated and theorganic phase was concentrated by distillation under vacuum to give thetitle compound as a yellow oil (200.3 g, 443 mmol, 98% yield);

-   -   ¹H NMR (CDCl₃ 300 MHz) δ: 1.45 (s, 9H), 1.45-1.56 (m, 1H),        1.56-1.74 (m, 6H), 1.74-2.11 (m, 7H), 2.32-2.43 (m, 1H), 2.64        (t, 2H), 3.22-3.30 (m, 2H), 3.27 (s, 3H), 3.30-3.38 (m, 2H),        5.75-5.85 (m, br, 1H), 7.13 (d, 2H), 7.26 (d, 2H); LRMS (ES        positive): m/z 452 [M+H]⁺ (³⁵CI).

Preparation of(2S)-2-{[1-({[3-(4-Chlorophenyl)propyl]amino}carbonyl)-cyclopentyl]methyl}-4-methoxybutanoicacid and its sodium salt (6-A)

To a solution of Intermediate I-6c (9.6 g, 21.2 mmol) in dichloromethane(52 ml) was added trifluoroacetic acid (16.3 ml, 212 mmol) and theresultant solution was stirred at room temperature for 3.75 hours underan atmosphere of N₂. To the reaction was then added aqueous sodiumcarbonate solution (95 ml of a 10% w/v solution) with stirring until thepH of the aqueous layer was between pH 2 and 3. The layers were thenseparated and the organic layer was extracted with aqueous sodiumcarbonate solution (2×20 ml of a 10% w/v solution). The aqueous layerswere combined and saturated brine (80 ml) was then added, followed by2-butanone (40 ml). The layers were separated and the aqueous layer wasextracted again with 2-butanone (2×50 ml). The combined organic layerswere then dried by azeotropic distillation at atmospheric pressure to avolume of 70 ml whereupon crystallisation occurred and the mixture wasdiluted with 2-butanone (70 ml). The product was then collected byfiltration and dried at 50° C. for 65 hours under vacuum to give thecrude sodium salt of the title compound as a white solid (5.76 g) thatwas then purified by recrystallisation as follows. To the crude productwas added ethyl acetate (87 ml) and ethanol (13 ml) and the remaininginsoluble material was removed by filtration. The ethanol was thenremoved by azeotropic distillation at atmospheric pressure (to remove110 ml of solvent) and replaced with ethyl acetate (145 ml) whereuponcrystallisation occurred. The resultant crystallised product was thencollected by filtration under vacuum to give the pure sodium salt of thetitle product as a white crystalline solid (4.51 g, 10.8 mmol, 51%);m.p. (ethyl acetate) 214-216° C.;

-   -   ¹H NMR (DMSO-d₆ 300 MHz) δ: 1.26-1.58 (m, 8H), 1.62-1.74 (m,        3H), 1.74-1.86 (m, 1H), 1.91-2.07 (m, 3H), 2.57 (t, 2H), 3.03        (q, 2H), 3.10 (s, 3H), 3.13-3.27 (m, 2H), 7.22 (d, 2H), 7.29 (d,        2H), 9.16 (t, br, 1H); LRMS (ES negative); 789 [2M−H]⁻ (³⁵CI),        394 [M−H]⁻ (³⁵CI).

For analytical purposes the title product (i.e. the free acid) wasobtained by dissolving this sodium salt in water, acidified with 5 Mhydrochloric acid and extracted with dichloromethane. Removal of thesolvent by blowing a stream of nitrogen over the sample gave the titleproduct;

-   -   ¹H NMR (DMSO-d₆ 300 MHz) δ: 1.22-1.80 (m, 11H), 1.81-1.96 (m,        2H), 1.96-2.08 (m, 1H), 2.93-2.27 (m, 1H), 2.53 (t, 2H), 3.03        (q, 2H), 3.11 (s, 3H), 3.16-3.25 (m, 2H), 7.20 (d, 2H), 7.30 (d,        2H), 7.51 (t, 1H); LRMS (ES negative); 789 [2M−H]⁻ (³⁵CI), 394        [M−H]⁻ (³⁵CI); HPLC (column: ChiralPak AS (25×0.46 cm); mobile        phase: hexane/IPA/acetic acid (95/5/0.5 v/v/v); flow rate: 1.0        ml/min; temperature: ambient; injection volume: 20 μl;        detection: UV@ 220 nm; Sample concentration: 1.0 mg/ml prepared        in mobile phase) Retention Time: minor enantiomer 11.4 min        (5.7%), major enantiomer 14.3 min (94.3%).        Preparation of Mono-hydrate of the Sodium Salt of 6-A:

To the sodium salt of 6-A (200 mg) was added to 1 ml of a 3.9% water inisopropanol solution. The resulting slurry was stirred for 12 dayswhereupon it was isolated by filtration. The product gave the followingPXRD pattern listed in Table 5 below. TABLE 5 Angle Intensity % 2-Theta° % 3.552 30.8 7.154 8 9.526 3.1 10.359 15.7 10.608 14.3 11.03 5 12.3693.7 12.939 13.2 13.233 12.3 13.835 14.2 14.345 37.9 14.887 16 15.16 16.816.372 24.9 16.813 6.9 17.203 22.1 17.408 32.7 17.708 13.5 17.93 2918.313 12 18.545 23.9 18.811 14 19.7 34.2 19.978 100 20.273 90.6 20.62751.9 20.829 29.4 20.926 28.4 21.443 52.7 21.611 41.6 21.881 21.2 22.17424.3 22.472 47.1 22.881 35 23.141 23.2 23.478 15.1 24.088 13.9 24.31312.6 24.588 22.7 25.013 25.8 25.514 29.9 25.987 25.5 27.107 18.2 27.39530.6 27.869 19.2 28.716 21 28.788 19 28.989 27.2 30.232 13.4 30.672 1530.952 17.5 31.437 15.7 31.788 13.9 32.114 24.6 32.998 13.3 33.375 18.833.815 14 34.266 14.4 35.705 15.7 35.989 14.1 36.514 16.7 38.151 14.638.925 17 39.091 19 39.961 13Differential scanning calorimetry (DSC) was performed using a PerkinElmer DSC-7 instrument fitted with an automatic sample changer.Approximately 3 mg of the sample was accurately weighed into a 50microlitre aluminium pan and crimp sealed with a perforated lid. Thesamples were heated at 20° C./minute over the range 40° C. to 300° C.with a nitrogen gas purge. Dehydration events occurred at between 50 and150° C. and a main melt between 212 and 225° C. The skilled person willappreciate that the melting point may vary outside this range as aresult of sample impurity.Anhydrous Salt:

The sodium salt of compound 6-A gave the following PXRD pattern listedin Table 6 below. TABLE 6 Angle Intensity % 2-Theta ° % 5.463 12.2 6.654100 7.546 66 9.336 31.3 10.953 9.7 11.571 55.9 12.56 10.9 13.287 22.915.125 33.6 15.667 60.3 16.403 17.2 17.024 62.2 17.714 95.6 18.083 31.718.64 28.8 18.902 82.4 19.696 40.1 20.406 33.9 20.502 31.8 20.683 45.420.942 31.5 21.559 92.6 21.898 66.2 22.274 36.6 22.735 30 23.36 56.524.126 31.9 24.388 45.2 24.72 25.8 25.298 26.7 25.579 20.4 26.718 17.627.151 24.2 27.46 22.7 27.737 20.2 28.56 27.1 28.926 23.8 29.802 23.530.454 30.7 30.885 29.2 31.48 21 32.66 16.8 34.027 23.1 34.494 17.636.011 19 36.997 17.4 38.704 21.2 39.961 18.7

Biological Assays

The utility of the compounds of the present invention in the practice ofthe instant invention can be evidenced by activity in at least one ofthe protocols described hereinbelow.

5HT_(2c) Binding Procedure

Affinity of compounds at the serotonin 5HT_(2c) binding site isdetermined by competition binding in Swiss 3T3 mouse cells (availablefrom the American Type Culture Collection (ATCC), Manassas, Va.)transfected with the human 5HT_(2c) receptor against 3H-5HT. The methodis adapted from Roth et al., J. of Pharm. And Exp. Therap., 260(3),1362-1365 (1992). Cells are grown in DMEM high glucose medium,harvested, homogenized, centrifuged, and resuspended in 50 mM Tris-HCL.They are incubated at 37° C. for 15 minutes, centrifuged, and thenresuspended into assay buffer (50 mM Tris-HCl, 4 mM CaCl₂, 0.1% ascorbicacid, and 100 μM pargyline at pH 7.7) at 100 volumes per gram. Assaytubes contain 25 μL of 10 nM ³H-5HT (1 nM final conc.), and 25 μl ofvehicle (assay buffer), blank (10 μM mianserin), or test compound (10×final volume). 200 μl of tissue homogenate is added to each tube,vortexed, and incubated for 30 minutes at 37° C. Samples are thenrapidly filtered under vacuum with a Skatron™ cell harvester (availablefrom Molecular Devices Corporation, Sunnyvale, Calif.) using GF/Bfilters presoaked in 0.5% polyethyleneimine (PEI), and washed with 2×5mL cold 50 mM Tris-HCl. Filter mats are removed and counted in a WallacBetaplate counter (available from PerkinElmer Life Sciences,Gaithersburg, Md.). Percent inhibition of specific binding by testcompounds is used to calculate the Ki, or extrapolate concentration oftest compound necessary to inhibit one-half of the total specificbinding for each compound.

The following compounds from the Examples above demonstrated a Ki valuefor 5HT_(2c) binding in the range of 0.2 nM to 238 nM:

Example Nos. 1-B, 1-D, 1-E, 1-F, 1-G, 1-H, 1-1,1-J, 1-K, 1-L, 1-M, 1-O,1-P, 1-Q, 1-R, 1-S, 1-T, 1-U, 1-V, 1-W, 1-X, 1-Y, 1-Z, 1-AA, 1-BB, 1-DD,1-EE, 1-FF, 1-GG, 1-HH, 1-II, 1-JJ, 1-KK, 1-LL, 1-MM, 1-CC, 1-OO, 1-PP,1-QQ, 1-RR, 1-SS, 1-TT, 1-UU, 1-VV, 1-WW, 1-XX, 1-YY, 1-ZZ, 1-AB, 1-AC,1-AD, 1-AE, 1-AJ, 1-AK, 1-AL, 2-A, 2-C, 2-D, 2-E, 2-F, 2-G, 2-H, 2-I,2-L, 3-A, 3-C, 3-D, 4-A, 4-B, 4-D and 5-A. Example Nos. 1-NN, 5-B and5-C demonstrated Ki values greater than 500 nM and the remainingcompounds were not determined.

5HT_(2A) Binding Procedure

Affinity of compounds at the serotonin 5HT_(2A) binding site isdetermined by competition binding in NIH 3T3 mouse cells transfectedwith the rat 5HT_(2A) receptor using 125I-DOI. The method was adaptedfrom Leonhardt et al., Molecular Pharmacology, 42, 328-335 (1992).Frozen cell paste is homgenized in 50 mM tris-HCl buffer pH 7.4containing 2 mM MgCl₂ using a Polytron and centrifuged at 45000×g forten minutes. The resulting pellet is resuspended in fresh ice-cold 50 mMtris-HCl buffer pH 7.4 containing 2 mM MgCl₂ using a Polytron™ andcentrifuged again at 45000×g for ten minutes. The final pellet isresuspended in 50 mM tris-HCl buffer pH 7.4 containing 2 mM MgCl₂ at aconcentraion of 5 mg/mL. Wells in a 96 well plate contain 25 μL of 0.7nM ¹²⁵I-DOI (70 μM final conc.), and 25 μL of vehicle (assay buffer),blank (10 μM cinanserin), or test compound (10× final volume). 200 μl oftissue homogenate is added to each well and incubated for 15 minutes at37° C. on a shaker. Samples are then rapidly filtered under vacuum witha cell harvester (Skatron™) using GF/B filters presoaked in 0.5%polyethyleneimine (PEI), and washed with 2×5 mL cold 50 mM tris-HCl.Filter mats are removed, dried and counted in a Wallac Betaplatecounter. Concentration-response curves of the % inhibition of specificbinding and log concentration by test compounds was used to determinethe IC₅₀ for each compound and the Ki value calculated based on theCheng-Prusof equation (Ki=IC50/(1+(L/Kd)), where L is the concentrationof the radioligand used in the binding assay and the Kd is based onprevious saturation studies with the radioligand.

The following compounds from the Examples above demonstrated a Ki valuefor 5HT_(2a) binding in the range of 0.5 nM to 625 nM:

Example Nos. 1-B, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, 1-K, 1-L, 1-M, 1-O,1-P, 1-Q, 1-R, 1-S, 1-T, 1-U, 1-Z, 1-M, 1-BB, 1-CC, 1-EE, 1-FF, 1-GG,1-HH, 1-II, 1-JJ, 1-KK 1-LL, 1-MM, 1-OO, 1-PP, 1-QQ, 1-RR, 1-SS, 1-TT,1-AJ, 1-AK, 1-AL. 2-A, 2-C, 2-D, 2-E, 2-F, 2-G, 2-H, 2-I, 2-L, 3-A, 3-D,and 4-D. Example Nos. 1-NN and 1-UU demonstrated no binding activity andthe remaining compounds were not determined.

Functional Assay

Swiss 3T3 cells expressing r-5HT_(2C), r-5HT_(2A), h-5HT_(2C) orh-5HT_(2A) receptors are seeded at a density of 12,500 cells/well in 384well black/clear collagen-coated plates. Forty eight (48) hrs later thecells are loaded with the calcium sensitive dye, Fluo 4-AM (4 μMdissolved in DMSO containing pluronic acid) in serum free DMEM in thepresence of probenicid (2.5 mM) for 75 minutes at 37° C. in a CO₂incubator. Unincorporated dye is removed by washing 3 times with aHEPES-buffered saline containing probenicid (2.5 mM) using a Skatron™cell washer (final volume 30 μL).

Plates are added to a fluorometric imaging plate reader (FLIPR 384available from Molecular Devices Corporation) individually andfluorescence measurements are taken every 2 seconds over an 85 secondsperiod. Test compound additions are made simultaneously to all 384 wellsafter 20 seconds of baseline recording. Concentration-response curvesare generated using Graphpad Prism™ (available from GraphPad Software,Inc., San Diego, Calif.) and agonist efficacies are generated as % ofthe response to 10 μM 5-HT (considered as 100%). Estimation ofantagonist potencies (functional Kis) are generated by measuringinhibition of the test compound response to 5-HT (10 nM for 5-HT_(2C)and 50 nM for 5-HT_(2A)) and applying the Cheng Prusoff equation.

The functional data for the compounds listed in the Examples aboveutilizing the 5-HT_(2c) expressed NIH 3T3 cells is summarized below.

Example Nos. 1-A through 1-AL, 2-A through 2-L, 3-A through 3-D, 4-Athrough 4-D, and 5-A through 5-C acted as partial agonist having an EC₅₀value in a range of 0.016 μM to 7.0 μM for the 5-HT₂c expressed cellswith the exception of: (i) Example Nos. 1-PP and 2-F which acted as fullantagonists, (ii) Example Nos. 2-D, 2-H, 1-NN and 1-QQ whichdemonstrated no 5-HT_(2c) functional activity at 10 μM and (iii) ExampleNo. 1-ZZ which were not determined.

The functional data for the compounds listed in the Examples aboveutilizing the 5-HT_(2a) expressed NIH 3T3 cells is summarized below.

Example Nos. 1-A through 1-AL, 2-A through 2-L, 3-A through 3-D, 4-Athrough 4-D and 5-A through 5-C acted as partial agonist having an EC₅₀value in a range of 0.16 μM to 7.6 μM with the exception of: (i) ExampleNos. 1-S, 1-U, 1-Y, 1-FF, 1-GG, 1-HH, 1-11, 1-KK, 1-LL, 1-MM, 1-PP,1-SS, 1-UU, 1-VV, 1-WW, 1-XX, 1-YY, 1-AC, 1-AI, 2-E, 2-F, 2-G, 2-H, 2-I,3-D, 4-A, 4-B, 4-C, 4-D, 5-A, 5-B, and 5-C which acted as fullantagonists; (ii) Example Nos. 1-D, 1-F, 1-AG, 1-AK, 1-AL, 1-NN, and1-QQ which demonstrated no functional activity at 10 μM; and (iii)Example 1-ZZ which was not determined.

Example No. 1-NN demonstrated no functional activity with either the5-HT_(2a) or the 5-HT_(2c) expressed cells. Although the cis-isomer(Compound 1-NN) is not active, it does not necessarily suggest that thetrans-isomer would not demonstrate functional activities.

Spontaneous Food Intake

Wistar rats are administered test compound either orally orsubcutaneously in a 30% β-cyclodextrin vehicle 30 minutes prior to theonset of the dark cycle. Food intake is monitored using a computerizedsystem that monitors the intake of individual animals. Food intake ismonitored for at least 16 hours after administration of the testcompound.

Sexual Dysfunction EXAMPLE A Treatment of MED

Compounds of the present invention can be screened for effect of penileintracavernosal pressure (ICP) in the conscious male rat according tothe methods described herein.

ICP Protocol: Intra cavernosal pressure (ICP) can be measured in theconscious rat by means of telemetric recording. A catheter is surgicallyimplanted into the corpus cavernosum. The end of the catheter is linkedto a device, which senses, processes, and transmits informationdigitally from within the animal. A receiver converts theradio-frequency signal from the implant to a digital pulse stream thatis readable by a data collection system. The PC-based system collectstelemetred data from the animal.

Surgery:—Induce and maintain general anaesthesia using 5% Isoflurane® ina carrier gas of 0.5 L/min oxygen and 1 L/min nitrous oxide to induceanaesthesia, reducing to 2% Isoflurane for maintenance anaesthesia.Administer 5 mg/kg sub cutaneously (s.c.) Carprofen (Rimadyl® LargeAnimal Injection, 50 mg/ml, Pfizer Animal Health) at induction ofanaesthesia, at end of day of surgery and on the morning of first daypost-surgery to minimise pain and discomfort.

Implantation of corpus cavernosal probe:—Shave the skin of the ventralabdomen and extend to include the area around the penis and ventralscrotum. Clean and disinfect the shaved area. Place the rat in dorsalrecumbency. Make a mid-line incision from the external base of thepenis, running caudally for approximately 2 cm. Locate and expose theinternal structure of the penis and identify the corpus cavernosum. Makea mid-line laparotomy, approximately 4 cm in length to access theabdominal cavity. Pierce the abdominal wall via the caudal incision witha suitable trocar and cannula, taking care not to damage any internalorgans. Place the implant body in the abdominal cavity with the catheterorientated caudally and pass the catheter tip through the body wall viathe preplaced cannula. Implant used is model TA11PA-C40, 8 mm catheter,with modified 3 mm tip (Data Sciences International Inc.). Secure theimplant body to the abdominal wall using non-absorbable sutures andpartially close the abdominal incision. Reflect the tip of the peniscranially and retract the caudal incision to optimise the surgicalfield. Carefully isolate approximately 10 mm of the internal structureof the penis from the surrounding tissue. Carefully reflect the corpusspongiosum to one side to give access to the corpus cavernosum. Accessthe corpus cavernosum using a modified over-the-needle catheter topuncture the tunica. Introduce the catheter tip via the preplacedcatheter and advance until fully inserted. Carefully remove the accesscatheter and apply a suitable tissue adhesive to the insertion site.Observe for leakage. Close the subcutaneous fat layer in the caudalincision before closing with an appropriate absorbable suture. Instilapproximately 5 ml of warm saline through the abdominal incision andcomplete closure of the mid-line incision. Close the skin incision withan appropriate absorbable suture.

Postoperative care:—Measure food and water intake and monitor bodyweightdaily for at least 7 days post surgery, then 2-3 times weekly. GiveLectade® (Pfizer Animal Health) in drinking water for 3 days postsurgery. House rats singly, and transfer to reverse light/darkconditions 5 days post surgery. Named Veterinary Surgeon (or Deputy) toissue a certificate of fitness to continue 2 days post surgery. Startusing rats experimentally 7 days post surgery.

Experimental Procedure:—Perform experiment in room with reverselight/dark conditions. On day of experiment, place rat in home cage onreceiver pad (PhysioTel® Model RPC-1, Data Sciences International Inc.)and leave to acclimatise for approximately one hour. Ensure that the rathas food and water ad lib. Take baseline reading of intra cavernosalpressure (ICP) for approximately 5 minutes. Transfer the data via afloppy disk to an Excel spreadsheet. Inject the rat with compoundsubcutaneously or via the jugular vein catheter (JVC). If using the JVC,flush through with sterile saline after dosing and seal with asaline/glucose lock solution. The interval between administration ofcompound and ICP measurement will vary with the compound to be tested.An interval of 30-60 min post s.c. injection is a good guide. The testcompounds were dissolved in 50% β-cyclodextrin in saline. They wereadministered at a dose of 5-10 mg/kg subcutaneously (s.c.). Apomorphinehydrochloride hemihydrate (Sigma A-4393) at 60 μg/kg s.c. was used as apositive control as it has pro-erectile properties. Record ICP over a 15minute period, starting at 30 minutes post injection i.e. from 30 to 35minutes and repeat for two further 15 minute periods commencing at 60minutes post injection and 120 minutes post injection respectively.Record ICP for 15 minutes. A signal from the receiver pad feeds throughto the Data Exchange Matrix® and hence to the software (Dataquest ART®acquisition system, Data Sciences International Inc.). Transfer the datavia a floppy disk to an Excel spreadsheet for analysis.

EXAMPLE B Compounds of Formula (I) in Combination with PDE5i forTreatment of MED

The effects of concomitant administration of a compound of the presentinvention in combination with a PDE5 inhibitor on the penileintracavernosal pressure (ICP) in an anaesthetised rabbit model oferection can be measured according to the following protocol.

Experimental Protocol

Male New Zealand rabbits (˜2.5 kg) are pre-medicated with a combinationof Medetomidine (Domitor®) 0.5 ml/kg inramuscularly (i.m.), and Ketamine(Vetalar®) 0.25 ml/kg i.m. whilst maintaining oxygen intake via a facemask. The rabbits are tracheotomised using a Portex™ uncuffedendotracheal tube 3 ID (internal diameter), connected to ventilator andmaintained at a ventilation rate of 30-40 breaths per minute, with anapproximate tidal volume of 18-20 ml, and a maximum airway pressure of10 cm H₂O. Anaesthesia was then switched to Isoflurane® and ventilationcontinued with O₂ at 2 litres/min. The right marginal ear vein wascannulated using a 23G or 24G catheter, and Lactated Ringer solutionperfused at 0.5 ml/min. The rabbit was maintained at 3% Isofluraneduring invasive surgery, dropping to 2% for maintenance anaesthesia. Theleft jugular vein was exposed, isolated and then cannulated with a PVCcatheter (17 gauge/17G) for the infusion of drugs and the testcompounds.

The left groin area of the rabbit was shaved and a vertical incision wasmade approximately 5 cm in length along the thigh. The femoral vein andartery were exposed, isolated and then cannulated with a PVC catheter(17G) for the infusion of drugs and compounds. Cannulation was repeatedfor the femoral artery, inserting the catheter to a depth of 10 cm toensure that the catheter reached the abdominal aorta. This arterialcatheter was linked to a Gould system to record blood pressure. Samplesfor blood gas analysis were also taken via the arterial catheter.Systolic and diastolic pressures were measured, and the mean arterialpressure calculated using the formula (diastolic x2+systolic)÷3. Heartrate was measured via the pulse oxymeter and Po-ne-mah data acquisitionsoftware system (Ponemah Physiology Plafform, Gould Instrument SystemsInc).

A ventral midline incision was made into the abdominal cavity. Theincision was about 5 cm in length just above the pubis. The fat andmuscle was bluntly dissected away to reveal the hypogastric nerve whichruns down the body cavity. It was essential to keep close to the sidecurve of the pubis wall in order to avoid damaging the femoral vein andartery which lie above the pubis. The sciatic and pelvic nerves liedeeper and were located after further dissection on the dorsal side ofthe rabbit. Once the sciatic nerve is identified, the pelvic nerve waseasily located. The term pelvic nerve is loosely applied; anatomy bookson the subject fail to identify the nerves in sufficient detail.However, stimulation of the nerve causes an increase in intracavernosalpressure and cavernosal blood flow, and innervation of the pelvicregion. The pelvic nerve was freed away from surrounding tissue and aHarvard bipolar stimulating electrode was placed around the nerve. Thenerve was slightly lifted to give some tension, then the electrode wassecured in position. Approximately 1 ml of light paraffin oil was placedaround the nerve and electrode. This acts as a protective lubricant tothe nerve and prevents blood contamination of the electrode. Theelectrode was connected to a Grass S88 Stimulator. The pelvic nerve wasstimulated using the following parameters: −5V, pulse width 0.5 ms,duration of stimulus 20 seconds with a frequency of 16 Hz. Reproducibleresponses were obtained when the nerve was stimulated every 15-20minutes. Several stimulations using the above parameters were performedto establish a mean control response. The compound(s) to be tested wereinfused, via the jugular vein, using a Harvard 22 infusion pump allowinga continuous 15 minute stimulation cycle. The skin and connective tissuearound the penis was removed to expose the penis. A catheter set(Insyte-W, Becton-Dickinson 20 Gauge 1.1×48 mm) was inserted through thetunica albica into the left corpus cavernosal space and the needleremoved, leaving a flexible catheter. This catheter was linked via apressure transducer (Ohmeda 5299-04) to a Gould system to recordintracavernosal pressure (ICP). Once an intracavernosal pressure wasestablished, the catheter was sealed in place using Vetbond (tissueadhesive, 3M). Heart rate was measured via the pulse oxymeter andPo-ne-mah data acquisition software system (Ponemah Physiology Plafform,Gould Instrument Systems Inc).

Intracavernosal blood flow was recorded either as numbers directly fromthe Flowmeter using Po-ne-mah data acquisition software (PonemahPhysiology Plafform, Gould Instrument Systems Inc), or indirectly fromGould chart recorder trace. Calibration was set at the beginning of theexperiment (0-125 ml/min/100 g tissue).

All data are reported as mean±s.e.m. (standard error of the mean).Significant changes were identified using Student's t-tests. The testcompounds were dissolved in 50% β-cyclodextrin in saline. They wereadministered at a dose of 5-10 mg/kg subcutaneously (s.c.).

Using the protocol described hereinbefore beneficial effects on ICP canbe demonstrated for the concomitant administration of a compound of thepresent invention (5-10 mg/kg s.c.) and a selective inhibitor of PDE5(3-ethyl-5-{5-[4-ethylpiperzino)sulphonyl-2-propoxyphenyl}-2-(2-pyridylmethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-7-one(as described in WO98/491066) (1 mg/kg i.v. (intravenously)). Thesestudies suggest that there are a number of clinical benefits ofconcomitant administration of a PDE5 inhibitor and a compound of formula(I). Such benefits include increased efficacy and opportunities to treatMED subgroups that do not respond to other MED mono-therapies.

EXAMPLE C Treatment of FSAD

Serotonin 5HT2C receptor agonists potentiate pelvic nerve-stimulatedincreases in female genital blood flow in the anaesthetised rabbit modelof sexual arousal.

The normal sexual arousal response consists of a number of physiologicalresponses that are observed during sexual excitement. These changes suchas vaginal, labial and clitoral engorgement result from increases ingenital blood flow. Engorgement leads to increased vaginal lubricationvia plasma transudation, increased vaginal compliance (relaxation ofvaginal smooth muscle) and increases in vaginal and clitoralsensitivity.

Female sexual arousal disorder (FSAD) is a highly prevalent sexualdisorder affecting up to 40% of pre-, peri- and postmenopausal (±HRT)women. The primary consequence of FSAD is reduced genital engorgement orswelling which manifests itself as a lack of vaginal lubrication and alack of pleasurable genital sensation. Secondary consequences includereduced sexual desire, pain during intercourse and difficulty inachieving orgasm. The most common cause of FSAD is decreased genitalblood flow resulting in reduced vaginal, labial and clitoral engorgement(Berman, J., Goldstein, I., Werbin, T. et al. (1999a). Double blindplacebo controlled study with crossover to assess effect of sildenafilon physiological parameters of the female sexual response. J. Urol.,161, 805; Goldstein, I. & Berman, J. R. (1998). Vasculogenic femalesexual dysfunction: vaginal engorgement and clitoral erectileinsufficiency syndromes. Int. J. Impot. Res., 10, S84-S90; Park, K.,Goldstein, I., Andry, C., et al. (1997). Vasculogenic female sexualdysfunction: The hemodynamic basis for vaginal engorgement insufficiencyand clitoral erectile insufficiency. Int. J. Impotence Res., 9, 27-37;Werbin, T., Salimpour, P., Berman, L., et al. (1999). Effect of sexualstimulation and age on genital blood flow in women with sexualstimulation. J. Urol., 161, 688).

As explained herein, the present invention provides a means forrestoring or potentiating the normal sexual arousal response in womensuffering from FSAD, by enhancing genital blood flow.

Method

Female New Zealand rabbits (˜2.5 kg) were pre-medicated with acombination of Medetomidine (Domitor®) 0.5 ml/kg intramuscularly (i.m.),and Ketamine (Vetalar®) 0.25 ml/kg i.m. whilst maintaining oxygen intakevia a face mask. The rabbits were tracheotomised using a Portex™uncuffed endotracheal tube 3 ID (internal diameter), connected toventilator and maintained at a ventilation rate of 30-40 breaths perminute, with an approximate tidal volume of 18-20 ml, and a maximumairway pressure of 10 cm H₂O. Anaesthesia was then switched toIsoflurane® and ventilation continued with O₂ at 2 l/min. The rightmarginal ear vein was cannulated using a 23G or 24G catheter, andLactated Ringer solution perfused at 0.5 ml/min. The rabbit wasmaintained at 3% Isoflurane® during invasive surgery, dropping to 2% formaintenance anaesthesia.

The left groin area of the rabbit was shaved and a vertical incision wasmade approximately 5 cm in length along the thigh. The femoral vein andartery were exposed, isolated and then cannulated with a PVC catheter(17G) for the infusion of drugs and compounds. Cannulation was repeatedfor the femoral artery, inserting the catheter to a depth of 10 cm toensure that the catheter reached the abdominal aorta. This arterialcatheter was linked to a Gould system to record blood pressure. Samplesfor blood gas analysis were also taken via the arterial catheter.Systolic and diastolic pressures were measured, and the mean arterialpressure calculated using the formula (diastolic x2+systolic)÷3. Heartrate was measured via the pulse oxymeter and Po-ne-mah data acquisitionsoftware system (Ponemah Physiology Platform, Gould Instrument SystemsInc).

A ventral midline incision was made into the abdominal cavity. Theincision was about 5 cm in length just above the pubis. The fat andmuscle was bluntly dissected away to reveal the hypogastric nerve whichruns down the body cavity. It was essential to keep close to the sidecurve of the pubis wall in order to avoid damaging the femoral vein andartery, which lie above the pubis. The sciatic and pelvic nerves liedeeper and were located after further dissection on the dorsal side ofthe rabbit. Once the sciatic nerve is identified, the pelvic nerve waseasily located. The term pelvic nerve is loosely applied; anatomy bookson the subject fail to identify the nerves in sufficient detail.However, stimulation of the nerve causes an increase in vaginal andclitoral blood flow, and innervation of the pelvic region. The pelvicnerve was freed away from surrounding tissue and a Harvard bipolarstimulating electrode was placed around the nerve. The nerve wasslightly lifted to give some tension, then the electrode was secured inposition. Approximately 1 ml of light paraffin oil was placed around thenerve and electrode. This acts as a protective lubricant to the nerveand prevents blood contamination of the electrode. The electrode wasconnected to a Grass S88 Stimulator. The pelvic nerve was stimulatedusing the following parameters: −5V, pulse width 0.5 ms, duration ofstimulus 10 seconds and a frequency range of 2 to 16 Hz. Reproducibleresponses were obtained when the nerve was stimulated every 15-20minutes. A frequency response curve was determined at the start of eachexperiment in order to determine the optimum frequency to use as asub-maximal response, normally 4 Hz. A ventral midline incision wasmade, at the caudal end of the pubis, to expose the pubic area.Connective tissue was removed to expose the tunica of the clitoris,ensuring that the wall was free from small blood vessels. The externalvaginal wall was also exposed by removing any connective tissue. Onelaser Doppler flow probe was inserted 3 cm into the vagina, so that halfthe probe shaft was still visible. A second probe was positioned so thatit lay just above the external clitoral wall. The position of theseprobes was then adjusted until a signal was obtained. A second probe wasplaced just above the surface of a blood vessel on the external vaginalwall. Both probes were clamped in position.

Test Compounds

8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one,which corresponds to Compound 75 of Chaki and Nakazato—Expert Opin.Ther. Patents (2001), 11(11):1677-1692 (see Section 3.9-5HT_(2c) on page1687 and FIG. 7 on page 1686), or Compound (6) of Isaac—Drugs of theFuture (2001), 26(4):383-393 (see FIG. 2 on page 385).

8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onewas dissolved in 50% β-cyclodextrin in saline. It was administered at adose of 5 mg/kg subcutaneously (s.c.).

Data Recordal

Vaginal and clitoral blood flow was recorded either as numbers directlyfrom the Flowmeter using Po-ne-mah data acquisition software (PonemahPhysiology Platform, Gould Instrument Systems Inc), or indirectly fromGould chart recorder trace. Calibration was set at the beginning of theexperiment (0-125 ml/min/100 g tissue). All data are reported asmean±standard error of the mean (s.e.m.). Significant changes wereidentified using Student's t-tests.

Results

The serotonin 5HT2C receptor agonist(8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one;5 mg/kg s.c.) acts as a potent enhancer of pelvic-nerve stimulated (PNS)increases in vaginal and clitoral blood flow in the anaesthetised rabbit(see Table 8 below). The potentiation was significant 30mins after s.c.dosing and remained elevated for circa 1 hr. The 5HT2c agonist had noeffect on basal genital blood flow in the absence of PNS (see Table 8below). This reinforces our view that a 5HT2c receptor agonist willenhance the arousal response by potentiating the mechanism(s) thatcontrol sexual arousal/genital blood flow, thereby treating FSAD, andwill not induce arousal in the absence of sexual stimulation. Sincethese agents also enhance clitoral blood flow it is likely that theywill be effective in the treatment of orgasmic disorders.

Table 8 below illustrates that8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one(5 mg/kg s.c.) potentiates pelvic nerve stimulated increases in genitalblood flow circa 35% after subcutaneous administration in theanaesthetised rabbit model of sexual arousal. TABLE 8 Time afterinjection of Compound Pelvic nerve 8,9-dichloro- stimulated2,3,4,4a-tetrahydro- Unstimulated increases Compound- 1H-pyrazino[1,2-vaginal in vaginal induced a]quinoxalin- blood flow blood flowpotentiation of 5(6H)-one (Laser Doppler (Laser Doppler stimulatedvaginal (min) units) units) blood flow Pre dose 148 +/− 6 241 +/− 10 —15 185 292 21 30 162 325 34 45 150 295 22 60 127 325 34 75 137 252  4 90132 247  2

1. A compound of Formula (IA)

wherein X and Y are CR and Z is N, or X is N and Y and Z are CR, where Rfor each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; at least one of R^(1a), R^(1b), R^(1d), and R^(1e) isindependently selected from the group consisting of halogen, nitro,amino, cyano, —C(O)NH₂, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl,(C₁-C₄) alkoxy, and halo-substituted(C₁-C₄)alkoxy, or R^(1a) and R^(1b)taken together form a five- or six-membered, aromatic or partially orfully saturated fused ring, or R^(1a) taken together with R^(2a) orR^(2b) forms a five- or six-membered, fully saturated fused ring; R^(1c)is hydrogen; R^(2a) and R^(2b) are each independently hydrogen,(C₁-C₄)alkyl, partially or fully saturated (C₃-C₆)cycloalkyl, or one ofwhich taken together with R^(1a) forms a five- or six-membered, fullysaturated fused ring; n is 0, 1, or 2; R^(3a) and R^(3b) are eachindependently hydrogen, (C₁-C₄)alkyl, or (C₁-C₄)alkyl substituted withhydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ is hydrogen, hydroxy,(C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxy or cyano,(C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,(C₃-C₄)alkenyl, or an amino-protecting group; a nitrogen oxide thereof,a prodrug of said compound or said nitrogen oxide; a pharmaceuticallyacceptable salt of said compound, said nitrogen oxide, or said prodrug,or a solvate or hydrate of said compound, said nitrogen oxide, saidprodrug, or said salt.
 2. The compound of claim 1 wherein X and Y are CRand Z is N, or X is N and Y and Z are CR, where R for each occurrence ishydrogen, halogen, or (C₁-C₄)alkyl; (i) R^(1a) is halogen, (C₁-C₄)alkyl,trifluoromethyl, methoxy, or trifluoromethoxy, and R^(1b), R^(1d) andR^(1e) are each hydrogen, (ii) R^(1b) is halogen, methyl, or methoxy andR^(1a), R^(1d) and R^(1e) are each hydrogen, (iii) R^(1a) and R^(1b) areeach independently halogen or methyl and R^(1d) and R^(1e) are eachhydrogen, (iv) R^(1b) and R^(1d) are each independently halogen ormethyl and R^(1a) and R^(1e) are each hydrogen, (v) R^(1a) and R^(1d)are each independently halogen or methyl and R^(1b), and R^(1e) are eachhydrogen, (vi) R^(1a) and R^(1e) are each independently halogen ormethyl and R^(1b) and R^(1d) are each hydrogen, or (vii) R^(1a), R^(1b)and R^(1d) are each independently halogen or methyl and R^(1e) ishydrogen; W is oxy or amino; n is 1 or 2; R^(2a) and R^(2b) are eachindependently methyl or hydrogen; R^(3a) and R^(3b) are eachindependently hydrogen or (C₁-C₂)alkyl; and R⁴ is hydrogen or(C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of said compound orsaid nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt. 3.The compound of claim 1 wherein Z is N; X is CH; Y is CR, where R ishydrogen or methyl; (i) R^(1a) is halogen, (C₁-C₄)alkyl,trifluoromethyl, methoxy, or trifluoromethoxy, and R^(1b), R^(1d) andR^(1e) are each hydrogen, (ii) R^(1b) is halogen, methyl or methoxy andR^(1a), R^(1d) and R^(1e) are each hydrogen, (iii) R^(1a) and R^(1b) areeach independently halogen or methyl and R^(1d) and R^(1e) are eachhydrogen, (iv) R^(1b) and R^(1d) are each independently halogen ormethyl and R^(1a) and R^(1e) are each hydrogen, (v) R^(1a) and R^(1d)are each independently halogen or methyl and R^(1b) and R^(1e) are eachhydrogen, (vi) R^(1a) and R^(1e) are each independently halogen ormethyl and R^(1b) and R^(1d) are each hydrogen, or (vii) R^(1a), R^(1b)and R^(1d) are each independently halogen or methyl and R^(1e) ishydrogen; W is oxy or amino; n is 1; R^(2a) and R^(2b) are eachindependently methyl or hydrogen; and R^(3a) is hydrogen, (2R)-methyl,or (2R)-ethyl; and R^(3b) is hydrogen; and R⁴ is hydrogen or(C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of said compound orsaid nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt. 4.The compound of claim 1 wherein X is N; Y is CR, where R is hydrogen ormethyl; Z is CH; (i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl,methoxy or trifluoromethoxy and R^(1b), R^(1d) and R^(1e) are eachhydrogen; (ii) R^(1b) is halogen or methoxy and R^(1a), R^(1d) andR^(1e) are each hydrogen, (iii) R^(1b) and R^(1d) are each independentlyhalogen or methyl and R^(1a) and R^(1e) are each hydrogen, or (iv)R^(1a) and R^(1d) are each independently halogen or methyl and R^(1b)and R^(1e) are each hydrogen; W is amino; n is 1; R^(2a) and R^(2b) areeach independently methyl or hydrogen; R³, is hydrogen, (2R)-methyl, or(2R)-ethyl; and R^(3b) is hydrogen; and R⁴ is hydrogen or (C₁-C₄)alkyl;a nitrogen oxide thereof, a prodrug of said compound or said nitrogenoxide; a pharmaceutically acceptable salt of said compound, saidnitrogen oxide, or said prodrug, or a solvate or hydrate of saidcompound, said nitrogen oxide, said prodrug, or said salt.
 5. Thecompound of claim 1 selected from the group consisting of2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, 2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 6. The compound of claim 1 selectedfrom the group consisting of2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, 2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimid ine, 2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimid ine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 7. The compound of claim 1 selectedfrom the group consisting of2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,hydrochloride;(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,hydrochloride;(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate;2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimid ine, hydrochloride;2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;and 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride.
 8. A pharmaceutical composition comprising (1) a compoundof Formula (IA)

wherein X and Y are CR and Z is N, or X is N and Y and Z are CR, where Rfor each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; at least one of R^(1a), R^(1b), R^(1d), and R^(1e) isindependently selected from the group consisting of halogen, nitro,amino, cyano, —C(O)NH₂, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl,(C₁-C₄) alkoxy, and halo-substituted(C₁-C₄)alkoxy, or R^(1a) and R^(1b)taken together form a five- or six-membered, aromatic or partially orfully saturated fused ring, or R^(1a) taken together with R^(2a) orR^(2b) forms a five- or six-membered, fully saturated fused ring; R^(1c)is hydrogen; R^(2a) and R^(2b) are each independently hydrogen,(C₁-C₄)alkyl, partially or fully saturated (C₃-C₆)cycloalkyl, or one ofwhich taken together with R^(1a) forms a five- or six-membered, fullysaturated fused ring; n is 0, 1, or 2; R^(3a) and R^(3b) are eachindependently hydrogen, (C₁-C₄)alkyl, or (C₁-C₄)alkyl substituted withhydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ is hydrogen, hydroxy,(C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxy or cyano,(C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,(C₃-C₄)alkenyl, or an amino-protecting group; a nitrogen oxide thereof,a prodrug of said compound or said nitrogen oxide; a pharmaceuticallyacceptable salt of said compound, said nitrogen oxide, or said prodrug,or a solvate or hydrate of said compound, said nitrogen oxide, saidprodrug, or said salt; and (2) a pharmaceutically acceptable excipient,diluent, or carrier
 9. The composition of claim 8 wherein said compoundof Formula (IA) is a compound where X and Y are CR and Z is N, or X is Nand Y and Z are CR, where R for each occurrence is hydrogen, halogen, or(C₁-C₄)alkyl; (i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl,methoxy, or trifluoromethoxy, and R^(1b), R^(1d) and R^(1e) are eachhydrogen, (ii) R^(1b) is halogen, methyl, or methoxy and R^(1a), R^(1d)and R^(1e) are each hydrogen, (iii) R^(1a) and R^(1b) are eachindependently halogen or methyl and R^(1d) and R^(1e) are each hydrogen,(iv) R^(1b) and R^(1d) are each independently halogen or methyl andR^(1a) and R^(1e) are each hydrogen, (v) R^(1a) and R^(1d) are eachindependently halogen or methyl and R^(1b), and R^(1e) are eachhydrogen, (vi) R^(1a) and R^(1e) are each independently halogen ormethyl and R^(1b) and R^(1d) are each hydrogen, or (vii) R^(1a), R^(1b)and R^(1d) are each independently halogen or methyl and R^(1e) ishydrogen; W is oxy or amino; n is 1 or 2; R^(2a) and R^(2b) are eachindependently methyl or hydrogen; R^(3a) and R^(3b) are eachindependently hydrogen or (C₁-C₂)alkyl; and R⁴ is hydrogen or(C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of said compound orsaid nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt. 10.The composition of claim 8 wherein said compound of Formula (IA) is acompound where Z is N; X is CH; Y is CR, where R is hydrogen or methyl;(i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl, methoxy, ortrifluoromethoxy, and R^(1b), R^(1d) and R^(1e) are each hydrogen, (ii)R^(1b) is halogen or methoxy and R^(1a), R^(1d) and R^(1e) are eachhydrogen, (iii) R^(1a) and R^(1b) are each independently halogen ormethyl and R^(1d) and R^(1e) are each hydrogen, (iv) R^(1b) and R^(1d)are each independently halogen or methyl and R^(1a) and R^(1e) are eachhydrogen, (v) R^(1a) and R^(1d) are each independently halogen or methyland R^(1b) and R^(1e) are each hydrogen, (vi) R^(1a) and R^(1e) are eachindependently halogen or methyl and R^(1b) and R^(1d) are each hydrogen,or (vii) R^(1a), R^(1b) and R^(1d) are each independently halogen ormethyl and R^(1e) is hydrogen; W is oxy or amino; n is 1; R^(2a) andR^(2b) are each independently methyl or hydrogen; and R^(3a) ishydrogen, (2R)-methyl, or (2R)-ethyl; and R^(3b) is hydrogen; and R⁴ ishydrogen or (C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of saidcompound or said nitrogen oxide; a pharmaceutically acceptable salt ofsaid compound, said nitrogen oxide, or said prodrug, or a solvate orhydrate of said compound, said nitrogen oxide, said prodrug, or saidsalt.
 11. The composition of claim 8 wherein said compound of Formula(IA) is a compound where X is N; Y is CR, where R is hydrogen or methyl;Z is CH; (i) R^(1a) is halogen, (C₁-C₄)alkyl, trifluoromethyl, methoxyor trifluoromethoxy and R^(1b), R^(1d) and R^(1e) are each hydrogen;(ii) R^(1b) is halogen, methyl, or methoxy and R^(1a), R^(1d) and R^(1e)are each hydrogen, (iii) R^(1b) and R^(1d) are each independentlyhalogen or methyl and R^(1a) and R^(1e) are each hydrogen, or (iv)R^(1a) and R^(1d) are each independently halogen or methyl and R^(1b)and R^(1e) are each hydrogen; W is amino; n is 1; R^(2a) and R^(2b) areeach independently methyl or hydrogen; R^(3a) is hydrogen, (2R)-methyl,or (2R)-ethyl; and R^(3b) is hydrogen; and R⁴ is hydrogen or(C₁-C₄)alkyl; a nitrogen oxide thereof, a prodrug of said compound orsaid nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt. 12.The pharmaceutical composition of claim 8 wherein said compound ofFormula (IA) is selected from the group consisting of2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimid ine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine, a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 13. The pharmaceutical composition ofclaim 8 wherein said compound of Formula (IA) is selected from the groupconsisting of 2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 14. The pharmaceutical composition ofclaim 8 wherein said pharmaceutically acceptable salt is selected fromthe group consisting of2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,hydrochloride;(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,hydrochloride;(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate;2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;and 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride.
 15. The pharmaceutical composition of claim 8, 9, 10, 11,12, 13, or 14 further comprising at least one other pharmaceuticalagent.
 16. The pharmaceutical composition of claim 15 wherein said atleast one other pharmaceutical agent is an anti-obesity agent.
 17. Thepharmaceutical composition of claim 16 wherein said anti-obesity agentis selected from the group consisting of an apo-B/MTP inhibitor, anMCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, asympathomimetic agent, a β₃ adrenergic receptor agonist, a dopamineagonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid1 receptor antagonist, a melanin concentrating hormone antagonist,leptin, a leptin analog, a leptin receptor agonist, a galaninantagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Yantagonist, a thyromimetic agent, dehydroepiandrosterone or an analogthereof, a glucocorticoid receptor agonist or antagonist, an orexinreceptor antagonist, a urocortin binding protein antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein, a ghrelin receptor antagonist, ahistamine 3 receptor antagonist or reverse agonist, and a neuromedin Ureceptor agonist.
 18. The pharmaceutical composition of claim 16 whereinsaid anti-obesity agent is selected from the group consisting oforlistat, sibutramine, bromocriptine, ephedrine, leptin, andpseudoephedrine.
 19. A pharmaceutical composition comprising (1) acompound of Formula (IB)

wherein X and Y are CR and Z is N, or X is N and Y and Z are CR, where Rfor each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, or (C₁-C₄)alkylamino; R^(1a),R^(1b), R^(1c), R^(1d) and R^(1e) are each independently hydrogen,halogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo-substituted (C₁-C₄)alkoxy, R^(1a) and R^(1b) taken together form afive- or six-membered, aromatic or partially or fully saturated fusedring, or R^(1a) taken together with R^(2a) or R^(2b) forms a five- orsix-membered, fully saturated fused ring; R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, partially or fully saturated(C₃-C₆)cycloalkyl, or one of which taken together with R^(1a) forms afive- or six-membered, fully saturated fused ring; n is 0 or 1; R^(3a)and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkylsubstituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ is hydrogen,hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxy or cyano,(C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl, or(C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of said compound orsaid nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt; (2)an antiobesity agent; and (3) a pharmaceutically acceptable excipient,diluent, or carrier.
 20. The pharmaceutical composition of claim 19wherein said anti-obesity agent is selected from the group consisting ofan apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a β₃ adrenergic receptoragonist, a dopamine agonist, a melanocyte-stimulating hormone receptoranalog, a cannabinoid 1 receptor antagonist, a melanin concentratinghormone antagonist, leptin, a leptin analog, a leptin receptor agonist,a galanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosteroneor an analog thereof, a glucocorticoid receptor agonist or antagonist,an orexin receptor antagonist, a urocortin binding protein antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein, a ghrelin receptor antagonist, ahistamine 3 receptor antagonist or reverse agonist, and a neuromedin Ureceptor agonist.
 21. The pharmaceutical composition of claim 19 whereinsaid anti-obesity agent is selected from the group consisting oforlistat, sibutramine, bromocriptine, ephedrine, leptin, andpseudoephedrine.
 22. The pharmaceutical composition of claim 19, 20 or21 wherein said compound of Formula (IB) is selected from the groupconsisting of 2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-[1-(3-fluoro-phenyl)-ethoxy]-4-piperazin-1-yl-pyrimidine,2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine, a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 23. The pharmaceutical composition ofclaim 22 wherein said pharmaceutically acceptable salt is selected fromthe group consisting of2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimid ine, hydrochloride;2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,hydrochloride;(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,hydrochloride;(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate;2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;and 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride.
 24. The pharmaceutical composition of claim 19, 20 or 21wherein said compound of Formula (IB) is selected from the groupconsisting of 2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimid ine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 25. A method for treating a 5-HT₂receptor-mediated disease, condition, or disorder in an animalcomprising the step of administering to said animal a therapeuticallyeffective amount of a compound of Formula of (IB)

X and Y are CR and Z is N, or X is N and Y and Z are CR, where R foreach occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted(C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a five-or six-membered, aromatic or partially or fully saturated fused ring, orR^(1a) taken together with R^(2a) or R^(2b) forms a five- orsix-membered, fully saturated, fused ring; R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, partially or fully saturated(C₃-C₆)cycloalkyl, or one of which taken together with R^(1a) forms afive- or six-membered, fully saturated fused ring; n is 0, 1, or 2;R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkyl substituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ ishydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxyor cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,or (C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of said compoundor said nitrogen oxide; a pharmaceutically acceptable salt of saidcompound, said nitrogen oxide, or said prodrug, or a solvate or hydrateof said compound, said nitrogen oxide, said prodrug, or said salt. 26.The method of claim 25 wherein said compound of Formula (IB) is selectedfrom the group consisting of2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimid ine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimid ine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine, a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 27. The method of claim 26 whereinsaid pharmaceutically acceptable salt is selected from the groupconsisting of 2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride; 2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride; 2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride;2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,hydrochloride;(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,hydrochloride;(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,hydrochloride;(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, fumarate;2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, hydrochloride;and 2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,hydrochloride.
 28. The method of claim 25 wherein said compound ofFormula (IB) is selected from the group consisting of2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, 2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 29. The method of claim
 25. 26, 27,or 28 wherein said 5-HT₂ receptor-mediated disease, condition ordisorder is a 5-HT_(2c) receptor-mediated disease, condition ordisorder.
 30. The method of claim 25, 26, 27, or 28 wherein said 5-HT₂receptor-mediated disease, condition, or disorder is selected from thegroup consisting of weight loss, obesity, bulimia, premenstrual syndromeor late luteal phase syndrome, depression, atypical depression, bipolardisorders, psychoses, schizophrenia, migraine, alcoholism, tobaccoabuse, panic disorder, anxiety, post-traumatic syndrome, memory loss,dementia of aging, social phobia, attention deficit hyperactivitydisorder, disruptive behavior disorders, impulse control disorders,borderline personality disorder, obsessive compulsive disorder, chronicfatigue syndrome, sexual dysfunction in males, sexual dysfunction infemales, anorexia nervosa, disorders of sleep, autism, seizuredisorders, epilepsy, mutism, spinal cord injury, damage of the centralnervous system, cardiovascular disorders, gastrointestinal disorders,diabetes insipidus, and type II diabetes.
 31. A method for treating orpreventing a 5-HT₂ receptor-mediated disease, condition, or disorder inan animal comprising the step of administering to said animal atherapeutically effective amount of a pharmaceutical composition ofclaim 8, 9, 10, 11, 12, 13, or
 14. 32. The method of claim 31 whereinsaid 5-HT₂ receptor-mediated disease, condition or disorder is a5-HT_(2c) receptor-mediated disease, condition or disorder.
 33. Themethod of claim 31 wherein said 5-HT₂ receptor-mediated disease,condition, or disorder is selected from the group consisting of weightloss, obesity, bulimia, premenstrual syndrome or late luteal phasesyndrome, depression, atypical depression, bipolar disorders, psychoses,schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder,anxiety, post-traumatic syndrome, memory loss, dementia of aging, socialphobia, attention deficit hyperactivity disorder, disruptive behaviordisorders, impulse control disorders, borderline personality disorder,obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males, sexual dysfunction in females, anorexia nervosa,disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinalcord injury, damage of the central nervous system, cardiovasculardisorders, gastrointestinal disorders, diabetes insipidus, and type IIdiabetes.
 34. A method for treating or preventing a 5-HT₂receptor-mediated disease, condition, or disorder in an animalcomprising the step of administering to said animal a therapeuticallyeffective amount of a pharmaceutical composition of claim 19, 20 or 21.35. The method of claim 34 wherein said pharmaceutical compositioncomprises a compound of Formula (IB) selected from the group consistingof 2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-(2-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-fluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3-methoxy-benzyloxy)-4-piperazin-1-yl-pyrimidine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,2-[1-(3-fluoro-phenyl)-ethoxy]4-methyl-6-piperazin-1-yl-pyrimidine,2-[1-(3-fluoro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(2-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]4-piperazin-1-yl-pyrimidine,2-[1-(3-chloro-phenyl)-ethoxy]-4-methyl-6-piperazin-1-yl-pyrimidine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine, a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 36. The method of claim 34 whereinsaid pharmaceutical composition comprises a compound of Formula (IB)selected from the group consisting of2-benzyloxy-4-methyl-6-piperazin-1-yl-pyrimidine,benzyl-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,benzyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,4-benzyloxy-2-piperazin-1-yl-pyrimidine,2-benzyloxy-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(3-chloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,(3-chloro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-fluoro-benzyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine,(3-fluoro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine,(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-amine,2-(2,3-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-piperazin-1-yl-pyrimidine,2-(2,5-difluoro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(2,5-dichloro-benzyloxy)-4-(2(R)-methyl-piperazin-1-yl)-pyrimidine,2-(3,5-dichloro-benzyloxy)-4-piperazin-1-yl-pyrimidine, and4-piperazin-1-yl-2-(2,3,5-trifluoro-benzyloxy)-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 37. The method of claim 34 whereinsaid 5-HT₂ receptor-mediated disease, condition or disorder is a5-HT_(2c) receptor-mediated disease, condition or disorder.
 38. Themethod of claim 34 wherein said 5-HT₂ receptor-mediated disease,condition, or disorder is selected from the group consisting of weightloss, obesity, bulimia, premenstrual syndrome or late luteal phasesyndrome, depression, atypical depression, bipolar disorders, psychoses,schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder,anxiety, post-traumatic syndrome, memory loss, dementia of aging, socialphobia, attention deficit hyperactivity disorder, disruptive behaviordisorders, impulse control disorders, borderline personality disorder,obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males, sexual dysfunction in females, anorexia nervosa,disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinalcord injury, damage of the central nervous system, cardiovasculardisorders, gastrointestinal disorders, diabetes insipidus, and type IIdiabetes.
 39. A pharmaceutical kit comprising (a) a dosage formcomprising a compound of Formula (IB)

X and Y are CR and Z is N, or X is N and Y and Z are CR, where R foreach occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted(C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a five-or six-membered, aromatic or partially or fully saturated fused ring, orR^(1a) taken together with R², or R^(2b) forms a five- or six-membered,fully saturated, fused ring; R^(2a) and R^(2b) are each independentlyhydrogen, (C₁-C₄)alkyl, partially or fully saturated (C₃-C₆)cycloalkyl,or one of which taken together with R^(1a) forms a five- orsix-membered, fully saturated fused ring; n is 0, 1, or 2; R^(3a) andR^(3b) are each independently hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkylsubstituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ is hydrogen,hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxy or cyano,(C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl, or(C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of the compound orthe nitrogen oxide; a pharmaceutically acceptable salt of the compound,the nitrogen oxide, or the prodrug, or a solvate or hydrate of thecompound, the nitrogen oxide, the prodrug, or the salt; and (b)instructions describing a method of using said dosage form to treat orprevent a 5-HT₂ receptor-mediated disease, condition, or disorder.
 40. Apharmaceutical kit comprising (a) a first unit dosage form comprising(i) a compound of Formula (IB)

 wherein X and Y are CR and Z is N, or X is N and Y and Z are CR, whereR for each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted(C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a five-or six-membered, aromatic or partially or fully saturated fused ring, orR^(1a) taken together with R^(2a) or R^(2b) forms a five- orsix-membered, fully saturated, fused ring; R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, partially or fully saturated(C₃-C₆)cycloalkyl, or one of which taken together with R^(1a) forms afive- or six-membered, fully saturated fused ring; n is 0, 1, or 2;R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkyl substituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ ishydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxyor cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,or (C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of the compoundor the nitrogen oxide; a pharmaceutically acceptable salt of thecompound, the nitrogen oxide, or the prodrug, or a solvate or hydrate ofthe compound, the nitrogen oxide, the prodrug, or the salt; and (ii) apharmaceutically acceptable carrier, excipient, diluent, or a mixturethereof; b) a second dosage form comprising (i) at least one additionalpharmaceutical agent selected from the group consisting of an apo-B/MTPinhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a β₃ adrenergic receptor agonist, adopamine agonist, a melanocyte-stimulating hormone receptor analog, acannabinoid 1 receptor antagonist, a melanin concentrating hormoneantagonist, leptin, a leptin analog, a leptin receptor agonist, agalanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosteroneor an analog thereof, a glucocorticoid receptor agonist or antagonist,an orexin receptor antagonist, a urocortin binding protein antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein, a ghrelin receptor antagonist, ahistamine 3 receptor antagonist or reverse agonist, and a neuromedin Ureceptor agonist; and (ii) a pharmaceutically acceptable carrier,excipient, diluent, or a mixture thereof; and c) a container.
 41. Amethod for treating or preventing a 5-HT₂ receptor-mediated disease,condition, or disorder comprising administering to an animal in need ofsuch treatment a) a therapeutically effective amount of a compound ofFormula (IB)

X and Y are CR and Z is N, or X is N and Y and Z are CR, where R foreach occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted(C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a five-or six-membered, aromatic or partially or fully saturated fused ring, orR^(1a) taken together with R^(2a) or R^(2b) forms a five- orsix-membered, fully saturated, fused ring; R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, partially or fully saturated(C₃-C₆)cycloalkyl, or one of which taken together with R^(1a) forms afive- or six-membered, fully saturated fused ring; n is 0, 1, or 2;R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkyl substituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ ishydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxyor cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,or (C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of the compoundor the nitrogen oxide; a pharmaceutically acceptable salt of thecompound, the nitrogen oxide, or the prodrug, or a solvate or hydrate ofthe compound, the nitrogen oxide, the prodrug, or the salt; and b) atherapeutically effective amount of at least one additionalpharmaceutical agent selected from the group consisting of an apo-B/MTPinhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a P3 adrenergic receptor agonist, adopamine agonist, a melanocyte-stimulating hormone receptor analog, acannabinoid 1 receptor antagonist, a melanin concentrating hormoneantagonist, leptin, a leptin analog, a leptin receptor agonist, agalanin antagonist, a lipase inhibitor, a bombesin agonist, aNeuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosteroneor an analog thereof, a glucocorticoid receptor agonist or antagonist,an orexin receptor antagonist, a urocortin binding protein antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,an AGRP, a ghrelin receptor antagonist, a histamine 3 receptorantagonist or reverse agonist, and a neuromedin U receptor agonist. 42.The method of claim 41 wherein said compound of Formula (IB), a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt, and said at least one additionalpharmaceutical agent is administered simultaneously.
 43. The method ofclaim 41 wherein said compound of Formula (IB), a nitrogen oxidethereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt, and said at least one additionalpharmaceutical agent is administered sequentially.
 44. The method ofclaim 41 wherein said compound of Formula (IB), a nitrogen oxidethereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt, and said at least one additionalpharmaceutical agent is administered as a single pharmaceuticalcomposition comprising said compound of Formula (IB), a nitrogen oxidethereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt, said at least one additionalpharmaceutical agent, and a pharmaceutically acceptable excipient,diluent, carrier or a mixture thereof.
 45. The method of claim 41wherein said compound of Formula (IB), a nitrogen oxide thereof, aprodrug of said compound or said nitrogen oxide; a pharmaceuticallyacceptable salt of said compound, said nitrogen oxide, or said prodrug,or a solvate or hydrate of said compound, said nitrogen oxide, saidprodrug, or said salt, and said at least one pharmaceutical agent isadministered as two separate pharmaceutical compositions comprising (i)a first composition comprising said compound of Formula (IB), a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt, and a pharmaceutically acceptableexcipient, diluent, or carrier; and (ii) a second composition comprisingsaid at least one pharmaceutical agent and a pharmaceutically acceptableexcipient, diluent, or carrier.
 46. The method of claim 45 wherein saidfirst composition and said second composition is administeredsimultaneously.
 47. The method of claim 45 wherein said firstcomposition and said second composition is administered sequentially.48. The method of claim 41, 42, 43, 44, 45, 46, or 47 wherein said 5-HT₂receptor-mediated disease, condition or disorder is a 5-HT_(2c)receptor-mediated disease, condition or disorder.
 49. A method ofincreasing lean meat content in an edible animal comprising the step ofadministering to said edible animal a lean meat increasing amount of acompound of Formula (IB)

X and Y are CR and Z is N, or X is N and Y and Z are CR, where R foreach occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, halogen, nitro, cyano, amino, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo-substituted(C₁-C₄)alkoxy, —C(O)NH₂, R^(1a) and R^(1b) taken together form a five-or six-membered, aromatic or partially or fully saturated fused ring, orR^(1a) taken together with R^(2a) or R^(2b) forms a five- orsix-membered, fully saturated, fused ring; R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, partially or fully saturated(C₃-C₆)cycloalkyl, or one of which taken together with R^(1a) forms afive- or six-membered, fully saturated fused ring; n is 0, 1, or 2;R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkyl substituted with hydroxy, fluoro, or (C₁-C₄)alkoxy; R⁴ ishydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkyl substituted with hydroxyor cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy-carbonyl,or (C₃-C₄)alkenyl; a nitrogen oxide thereof, a prodrug of the compoundor the nitrogen oxide; a pharmaceutically acceptable salt of thecompound, the nitrogen oxide, or the prodrug, or a solvate or hydrate ofthe compound, the nitrogen oxide, the prodrug, or the salt.
 50. A methodof increasing lean meat content in an edible animal comprising the stepof administering to said edible animal a lean meat increasing amount ofa pharmaceutical composition of claim 8, 9, 10, 11, 12, 13, 14, 15, 19,20, or
 21. 51. A compound of Formula (IC)

wherein X and Y are CR and Z is N, or X is N and Y and Z are CR, where Rfor each occurrence is hydrogen, halogen, (C₁-C₄)alkyl, amino, or(C₁-C₄)alkylamino; W is oxy, thio, amino, (C₁-C₄)alkylamino, oracetylamino; Q is a heteroaryl group selected from the group consistingof pyridin-2-yl, pyridin-3-yl, furan-3-yl, furan-2-yl, thiophen-2-yl,thiophen-3-yl, thiazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl,quinolin-2-yl, quinolin-3-yl, isoquinolin-3-yl, benzofuran-2-yl,benzofuran-3-yl, isobenzofuran-3-yl, benzothiophen-2-yl,benzothiophen-3-yl, indol-2-yl, indol-3-yl, 2H-imidazol-2-yl,oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-triazol-3-yl,and 1,2,4-oxathiazol-3-yl, where said heteroaryl group is optionallysubstituted with one to three substituents independently selected fromhalo, (C₁-C₄)alkyl or (C₁-C₄)alkyoxy; R²′ and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, or partially or fully saturated(C₃-C₆)cycloalkyl; R^(3a) and R^(3b) are each independently hydrogen,(C₁-C₄)alkyl, or (C₁-C₄)alkyl substituted with hydroxy, fluoro, or(C₁-C₄)alkoxy; R⁴ is hydrogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkylsubstituted with hydroxy or cyano, (C₁-C₄)alkylcarbonyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxy-carbonyl, or (C₃-C₄)alkenyl; a nitrogen oxide thereof, aprodrug of said compound or said nitrogen oxide; a pharmaceuticallyacceptable salt of said compound, said nitrogen oxide, or said prodrug,or a solvate or hydrate of said compound, said nitrogen oxide, saidprodrug, or said salt.
 52. The compound of claim 51 selected from thegroup consisting of 4-piperazin-1-yl-2-(pyridin-2-ylmethoxy)-pyrimidine,2-(6-methyl-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine, and2-(6-chloro-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 53. The compound of claim 51 selectedfrom the group consisting of2-(6-methyl-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine and2-(6-chloro-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine; a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 54. A method for treating orpreventing a 5-HT₂ receptor-mediated disease, condition, or disorder inan animal comprising the step of administering to said animal atherapeutically effective amount of a compound of claim 51, a nitrogenoxide thereof, a prodrug of said compound or said nitrogen oxide; apharmaceutically acceptable salt of said compound, said nitrogen oxide,or said prodrug, or a solvate or hydrate of said compound, said nitrogenoxide, said prodrug, or said salt.
 55. The method of claim 54 whereinsaid 5-HT₂ receptor-mediated disease, condition or disorder is a5-HT_(2c) receptor-mediated disease, condition or disorder.
 56. Themethod of claim 54 wherein said 5-HT₂ receptor-mediated disease,condition, or disorder is selected from the group consisting of weightloss, obesity, bulimia, premenstrual syndrome or late luteal phasesyndrome, depression, atypical depression, bipolar disorders, psychoses,schizophrenia, migraine, alcoholism, tobacco abuse, panic disorder,anxiety, post-traumatic syndrome, memory loss, dementia of aging, socialphobia, attention deficit hyperactivity disorder, disruptive behaviordisorders, impulse control disorders, borderline personality disorder,obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males, sexual dysfunction in females, anorexia nervosa,disorders of sleep, autism, seizure disorders, epilepsy, mutism, spinalcord injury, damage of the central nervous system, cardiovasculardisorders, gastrointestinal disorders, diabetes insipidus, and type IIdiabetes.
 57. A method for treating female sexual dysfunction (FSD)comprising the step of administering to a female in need thereof atherapeutically effective amount of a compound of claim
 1. 58. Themethod of claim 57 further comprising the step of administrating one ormore additional active agents for treating FSD.
 59. The method of claim58 wherein said one or more additional active agents is selected fromthe group consisting of (1) as estrogen receptor modulators, estrogenagonists, estrogen antagonists or combinations thereof; (2) testosteronereplacement agent, testosternone (Tostrelle), dihydrotestosterone,dehydroepiandrosterone (DHEA), a testosterone implant, or combinationsthereof; (3) estrogen, a combination of estrogen and medroxyprogesteroneor medroxyprogesterone acetate (MPA), or estrogen and methyltestosterone hormone replacement therapy agent; (4) one or moredopaminergic agents; (5) one or more of an NPY (neuropeptide Y)inhibitor; (6) one or more of a melanocortin receptor agonist ormodulator or melanocortin enhancer; (7) one or more of an NEP inhibitor;(8) one or more of a PDE inhibitor; and (9) one or more of a bombesinreceptor antagonist or modulator.
 60. The method of claims 57, 58 or 59wherein said FSD is female sexual arousal disorder (FSAD), femaleorgasmic disorder (FOD), hypoactive sexual desire disorder (HSDD), orsexual pain disorder.
 61. A method for treating male erectiledysfunction (MED) comprising the step of administering to a male in needthereof a therapeutically effective amount of a compound of claim 1.